Thiadiazole irak4 inhibitors

ABSTRACT

A compound of Formula (I):pharmaceutically acceptable salts thereof, deuterated analogs thereof, compositions thereof, and methods of treating disease using a compound thereof are disclosed.

FIELD

The present disclosure relates to novel compounds that are inhibitors ofthe kinase IRAK4. The disclosure also relates to methods for preparingthe compounds and to pharmaceutical compositions comprising suchcompounds.

BACKGROUND

Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threoninekinase which acts as a mediator in interleukin-1/Toll-like receptor(IL-1/TLR) signaling cascades. More particularly, IRAK4 is involved inactivation of adaptor protein myeloid differentiation primary responsegene 88 (MyD88) signaling cascades and is hypothesized to play a role ininflammatory and fibrotic disorders, such as rheumatoid arthritis (RA),inflammatory bowel disease (IBD), gout, Lyme disease, arthritis,psoriasis, pelvic inflammatory disease, systemic lupus erythematosus(SLE), Sjogren's syndrome, viral myocarditis,acute and chronic tissueinjury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis andkidney disease, including chronic kidney disease and diabetic kidneydisease. In addition, IRAK4 plays a role in certain cancers and ishypothesized to play a role in inflammation associated withgastrointestinal infections, including C. difficile. Signaling throughIL-1R/TLR results in the activation of MyD88 which recruits IRAK4 andIRAK1 to form a signaling complex. This complex then interacts with aseries of kinases, adaptor proteins, and ligases, ultimately resultingin the activation of nuclear factor kappa-light-chain-enhancer ofactivated B cells (NF-κB), activator protein-1 (AP1), cyclicAMP-responsive element-binding protein (CREB) and theinterferon-regulatory factors (IRFs), including IRF5 and IRF7, inducingthe generation of pro-inflammatory cytokines and type I interferons.

Therefore, inhibitors of IRAK4 may be useful in the treatment ofinflammatory and fibrotic disorders, such as rheumatoid arthritis (RA),inflammatory bowel disease (IBD), gout, Lyme disease, arthritis,psoriasis, pelvic inflammatory disease, systemic lupus erythematosus(SLE), Sjogren's syndrome, inflammation associated with gastrointestinalinfections, including C. difficile, viral myocarditis, acute and chronictissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitisand kidney disease, including chronic kidney disease and diabetic kidneydisease. (Joosten, L. A. B et al., TOLL-LIKE RECEPTORS AND CHRONICINFLAMMATION IN RHEUMATIC DISEASES: NEW DEVELOPMENTS, Nat. Rev.Rheumatol., 346|JUNE 2016 12; 344-357 Published online 12 May 2016)(Valaperti, A. et al., INNATE IMMUNE INTERLEUKIN-1RECEPTOR-ASSOCIATEDKINASE 4 EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5⁺CD11b⁺ MONOCYTEMIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circulation,128|SEPTEMBER 2013 14; 1542-1554), as well as Type I interferonopathies,such as Aicardi-Goutières syndrome, Familial chilblain lupus, andRetinal vasculopathy with cerebral leukodystrophy, (Lee-Kirsch et al.,TYPE I INTERFERONOPATHIES—AN EXPANDING DISEASE SPECTRUM OFIMMUNODYSREGULATION, Semin. Immunopathol. (2015) 37:349-357), (Leaf, I.A. et al., PERICYTE MYD88 AND IRAK4 CONTROL INFLAMMATORY AND FIBROTICRESPONSES TO TISSUE INJURY, The Journal of Clinical Investigation,127|JANUARY 2017 1; 321-334), (Seki, E. et al., TLR4 ENHANCES TGF-βSIGNALING AND HEPATIC FIBROSIS, Nature Medicine, 13|NOVEMBER 2007 11;1324-1332), (Garcia-Martinez, I. et al., HEPATOCYTE MITOCHONDRIAL DNADRIVES NONALCHOLIC STEATOHEPATITIS BY ACTIVATION OF TLR9, The Journal ofClinical Investigation, 126|MARCH 2016 3; 859-864).

In addition, certain cancers, including lymphomas, may contain one ormore mutations in the MYD88 adaptor protein, leading to a constitutivelyactive signaling cascade that may promote survival of tumor cells.(Kelly et al., IRAK4 inhibitors for autoimmunity and lymphoma, J. Exp.Med. 2015 Vol. 212 No. 13 2189-2201)

Therefore, an inhibitor of IRAK4 may be useful in the treatment ofcancers, including lymphomas.

There are currently no approved IRAK4 inhibiting pharmaceuticals.Therefore, it would be useful to provide an IRAK4 inhibiting compoundwith properties suitable for administration as a pharmaceutical agent toa mammal, particularly a human. Considerations for selecting apharmaceutical compound are multifactorial. Compound characteristicsincluding on-target potency, pharmacokinetics, pKa, solubility,stability (e.g., metabolic stability) and off-target liabilities arefrequently profiled.

WO2016210034, WO2016210036, WO2015150995, WO2016127024, and WO2016210037recite compounds said to be useful as IRAK4 inhibitors.

IRAK1 functions as a cytokine initiated by the binding of ligands toIL-1R and TLRs. Activation of the IL-1 and TLR signaling pathways can betriggered by a variety of stimuli, including recognition of microbialpathogens or products, such as LPS, the presence of reactive oxygenspecies, recognition of DNA damage, abnormalities in the tissue matrixcaused by chronic inflammation, and genetic factors, such asamplification of 1q21.3 and overproduction of S100A proteins.

The inflammatory cytokines sIL-17A, sIL-2, and sIL-6 are regulated byIRAK1, and inhibition of IRAK1 by the late-stage clinical compoundpacritinib suppresses induced immunglobulin synthesis in normal humanlymphocytes. In normal human monocytes, IRAK1 induces inflammatorycytokines upon LPS challenge. (See, for example, Singer, J. et al.INHIBITION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 1 (IRAK1) AS ATHERAPEUTIC STRATEGY, Oncotarget, Vol. 9, (No. 70), pp: 33416-33439(2018)). Therefore, there is strong evidence to support the role ofIRAK1 in a variety of inflammatory conditions.

SUMMARY OF THE INVENTION

Provided herein are compounds and pharmaceutical compositions useful asinhibitors of IRAK4 or IRAK1 or both IRAK4 and IRAK1. Some compounds ofthe disclosure may find use in pharmaceutical compositions, togetherwith at least one pharmaceutically acceptable excipient, for treating asubject in need thereof. Compounds of the present disclosure also havebeen found to inhibit production of pro-inflammatory cytokines TNFα,IL-6, IL-1β, IL-8, IL-12, IL-23 and type I interferons IFNα and IFNβ,all of which are mediators of inflammation and the immune response. Thedisclosure also provides compositions, including pharmaceuticalcompositions, kits that include the compounds, and methods of using andmaking the compounds.

In one embodiment of the disclosure, there is provided a compound ofFormula (I):

-   wherein “Het” is a bicyclic heteroaryl optionally substituted with    X;-   X is selected from —H, —F, —Cl, —Br, and —CN;-   R¹ and R² are each independently selected from:

a) C₁₋₁₀ alkyl optionally substituted with Z¹;

b) C₃₋₁₀ cycloalkyl optionally substituted with Z¹;

c) 5-10 membered heteroaryl optionally substituted with Z¹;

d) C₆₋₁₀ aryl optionally substituted with Z¹;

e) 4-12 membered heterocyclyl optionally substituted with Z¹; and

f) —H, —O—R¹², —C(O)-R¹², —C(O)O—R¹², —C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²),—N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹²,—N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹²)(R¹²),—NR¹²S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃,—S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹²—S(O)₂N(R¹²)(R¹²) orsulfoximine;

-   Z¹ is independently oxo, imino, sulfoximino, halo, —NO₂, —N₃, —CN,    C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈    haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)-R¹²,    —C(O)O—R¹², —C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), -—(R¹²)₂(R¹²)⁺,    —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹²)(R¹²),    —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)²N(R¹²)(R¹²), —NR¹²S(O)₂O(R¹²),    —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹²,    —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹²)(R¹²);-   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl,    heteroaryl or heterocyclyl is optionally substituted with Z^(1a);-   each Z^(1a) is independently oxo, imino, sulfoximino, halo, —NO₂,    —CN, —N₃, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl,    C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,    —C(O)—R¹², —C(O)N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺,    —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹²)(R¹²),    —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹²)(R¹²), —N(R¹²)S(O)₂O(R¹²),    —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹²,    —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹²)(R¹²);-   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl,    heteroaryl or heterocyclyl is optionally substituted with Z^(1b);-   each R¹² is independently H, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl;-   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or    heterocyclyl is optionally substituted with Z^(1a);-   each Z^(1b) is independently oxo, imino, sulfoximino, hydroxy, halo,    —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅    cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl, —O(C₁₋₉    alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅ cycloalkyl),    —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl),    —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl), —NH(C₂₋₆ alkynyl),    —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),    —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅    cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅    cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,    —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉    alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉    alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉    alkyl)(aryl), —N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉    alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl), —C(O)(C₂₋₆ alkenyl),    —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅ cycloalkyl), —C(O)(C₁₋₈ haloalkyl),    —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C₁₋₉    alkyl), —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅    cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),    —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉    alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl), —C(O)NH(C₃₋₁₅    cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),    —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,    —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆    alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂,    —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂,    —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl),    —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl),    —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl),    —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅    cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl),    —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl),    —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅    cycloalkyl), —NHC(O)NH(C₁₋₈ haloalkyl), —NHC(O)NH(aryl),    —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl),    —S(C₂₋₆ alkenyl), —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈    haloalkyl), —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉    alkyl), —N(C₁₋₉ alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂,    —S(O)(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl),    —S(O)(C₂₋₆ alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl),    —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉    alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅    cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),    —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl), or    —S(O)₂N(C₁₋₉ alkyl)₂;-   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is    optionally substituted with one or more halo, C₁₋₉ alkyl, C₁₋₈    haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅ cycloalkyl),    —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl),    —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl),    —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),    —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl),    —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl),    —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl),    —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl), S(O)₂(C₁₋₉ alkyl),    —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),    —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),    —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),    —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);-   or a pharmaceutically acceptable salt, stereoisomer, mixture of    stereoisomers, or deuterated analog thereof.

In one embodiment, “Het” is selected from:

In one embodiment, R¹ is C₁₋₁₀ alkyl optionally substituted with Z¹.

In another embodiment, R¹ is C₁₋₅ alkyl optionally substituted with —F,—OH, or —CN.

In another embodiment, R¹ is 4-8 membered heterocycle optionallysubstituted with Z¹.

In another embodiment, R¹ is oxetane, tetrahydrofuran or tetrahydropyranoptionally substituted with Z¹.

In another embodiment, R¹ is C₃₋₁₀ cycloalkyl optionally substitutedwith Z¹.

In still another embodiment, R¹ is C₃₋₁₀ cycloalkyl substituted with5-10 membered heteroaryl wherein said 5-10 membered heteroaryl isoptionally substituted with Z^(1a).

In another embodiment, R¹ is C₃₋₁₀ cycloalkyl substituted with C₁₋₃alkyl and said C₁₋₃ alkyl is further substituted with Z^(1a).

In another embodiment, R¹ is 5-10 membered heteroaryl optionallysubstituted with Z¹.

In one embodiment, R² is C₁₋₁₀ alkyl optionally substituted with Z¹.

In another embodiment, R² is C₁₋₁₀ alkyl optionally substituted with oneor more —F, —OH or combinations thereof.

In another embodiment, R² is C₃₋₁₀ cycloalkyl optionally substitutedwith Z¹.

In another embodiment, R² is C₃₋₈ cycloalkyl optionally substituted with—OH, —N(R¹²)C(O)(R¹²), —N(R¹²)C(O)O(R¹²), or —C(O)N(R¹²)(R¹²).

In another embodiment, R² is a 4-8 membered heterocyclyl optionallysubstituted with Z¹.

In another embodiment, R² is a 4-8 membered heterocyclyl substitutedwith —OH, —N(R¹²)C(O)(R¹²), —N(R¹²)C(O)O(R¹²), or —C(O)N(R¹²) (R¹²).

In another embodiment, R² is —C(O)—N(R¹²)(R¹²).

The disclosure also provides a compound of Formula (Ia):

-   wherein R¹ and R² are each independently selected from:

a) C₁₋₁₀ alkyl optionally substituted with Z¹;

b) C₃₋₁₀ cycloalkyl optionally substituted with Z¹;

c) 5-10 membered heteroaryl optionally substituted with Z¹;

d) C₆₋₁₀ aryl optionally substituted with Z¹;

e) 4-12 membered heterocyclyl optionally substituted with Z¹; and

f) —-H, —O—R¹², —C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²),—N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹²,—N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹²)(R¹²),—NR¹²S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃,—S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹²)(R¹²), or sulfoximine;

-   and wherein Z¹ is independently imino, sulfoximino oxo, halo, —NO₂,    —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl,    C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹²,    —C(O)O—R¹², —C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺,    —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹²)(R¹²),    —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R¹²),    —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹²,    —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹²)(R¹²);-   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl,    heteroaryl or heterocyclyl is optionally substituted with Z^(1a);

each Z^(1a) a is independently oxo, imino, sulfoximino halo, —NO₂, —CN,—N₃, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R¹²,—C(O)N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)—C(O)R¹²,—N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹²)(R¹²), N(R¹²)S(O)₂(R¹²),—N(R¹²)S(O)₂—N(R¹²)(R¹²), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,—OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹²or —S(O)₂N(R¹²)(R¹²);

-   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl,    heteroaryl or heterocyclyl is optionally substituted with Z^(1b);-   each R¹² is independently H, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl;-   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or    heterocyclyl is optionally substituted with Z^(1a);-   each Z^(1b) is independently imino, sulfoximino oxo, hydroxy, halo,    —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅    cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl, —O(C₁₋₉    alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅ cycloalkyl),    —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl),    —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl), —NH(C₂₋₆ alkynyl),    —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),    —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅    cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅    cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,    —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉    alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉    alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉    alkyl)(aryl), —N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉    alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl), —C(O)(C₂₋₆ alkenyl),    —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅ cycloalkyl), —C(O)(C₁₋₈ haloalkyl),    —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C₁₋₉    alkyl), —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅    cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),    —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉    alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl), —C(O)NH(C₃₋₁₅    cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),    —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,    —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆    alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂,    —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂,    —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl),    —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl),    —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl),    —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅    cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl),    —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl),    —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅    cycloalkyl), —NHC(O)NH(C₁₋₈ haloalkyl), —NHC(O)NH(aryl),    —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl),    —S(C₂₋₆ alkenyl), —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈    haloalkyl), —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉    alkyl), —N(C₁₋₉ alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂,    —S(O)(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl),    —S(O)(C₂₋₆ alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O(C₁₋₈ haloalkyl),    —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉    alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅    cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),    —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl), or    —S(O)₂N(C₁₋₉ alkyl)₂;-   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is    optionally substituted with one or more halo, C₁₋₉ alkyl, C₁₋₈    haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅ cycloalkyl),    —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl),    —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl),    —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),    —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl),    —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl),    —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl),    —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl), S(O)₂(C₁₋₉ alkyl),    —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),    —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),    —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),    —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);-   or a pharmaceutically acceptable salt, stereoisomer, mixture of    stereoisomers, or deuterated analog thereof.

In another embodiment the disclosure provides a pharmaceuticalcomposition comprising a compound of Formula (I) or (Ia) or apharmaceutically acceptable salt, stereoisomer, mixture of stereoisomersor deuterated analog thereof, together with a pharmaceuticallyacceptable carrier.

In still other embodiments the disclosure provides a method of treatingan inflammatory condition in a patient in need thereof, comprisingadministering to said patient a compound of Formula (I) or (Ia) or thecomposition comprising a compound of Formula (I) or (Ia).

In some embodiments the inflammatory condition is selected from IBD,SLE, Psoriasis and Rheumatoid Arthritis.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.,—(CH₂)₃CH₃), sec-butyl (i.e., —CH(CH₃)CH₂CH₃), isobutyl (i.e.,—CH₂CH(CH₃)₂) and tert-butyl (i.e., —C(CH₃)₃); and “propyl” includesn-propyl (i.e., —(CH₂)₂CH₃) and isopropyl (i.e., —CH(CH₃)₂).

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples ofalkenyl groups include ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term“alkynyl” also includes those groups having one triple bond and onedouble bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore hydrogen atoms are replaced by a halogen.

“Alkylthio” refers to the group “alkyl-S—”.

“Amino” refers to the group —NR^(y)R^(y) wherein each R^(y) isindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl or heteroaryl, each ofwhich is optionally substituted, as defined herein.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl, the resulting ringsystem is heteroaryl. If one or more aryl groups are fused with aheterocyclyl, the resulting ring system is heterocyclyl.

“Cyano” refers to the group —CN.

“Keto” or “oxo” refers to a group ═O.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NR^(y)R^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R^(y) and R^(z) are independentlyselected from the group consisting of hydrogen, alkyl, aryl, haloalkyl,or heteroaryl; each of which may be optionally substituted.

“Carboxyl” refers to —C(O)OH.

“Ester” refers to both —OC(O)R and —C(O)OR, wherein R is a substituent;each of which may be optionally substituted, as defined herein.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e., the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group. The term“heteroalkyl” includes unbranched or branched saturated chain havingcarbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may beindependently replaced with the same or different heteroatomic group.Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—,—S(O)—, —S(O)₂—, and the like, where R is H, alkyl, aryl, cycloalkyl,heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionallysubstituted. Examples of heteroalkyl groups include —OCH₃, —CH₂OCH₃,—SCH₃, —CH₂SCH₃, —NRCH₃, and —CH₂NRCH₃, where R is hydrogen, alkyl,aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may beoptionally substituted. As used herein, heteroalkyl include 1 to 10carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 heteroatoms, 1to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, oxygen, andsulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl,pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of thefused-heteroaryl rings include, but are not limited to,benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl,indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, andimidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via eitherring of the fused system. Any aromatic ring, having a single or multiplefused rings, containing at least one heteroatom, is considered aheteroaryl regardless of the attachment to the remainder of the molecule(i.e., through any one of the fused rings). Heteroaryl does notencompass or overlap with aryl as defined above.

“Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group,with one or more ring heteroatoms independently selected from nitrogen,oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenylgroups (i.e., the heterocyclyl group having at least one double bond),bicyclic heterocyclyl groups, bridged-heterocyclyl groups,fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclylmay be a single ring or multiple rings wherein the multiple rings may befused, bridged, or spiro. Any non-aromatic ring containing at least oneheteroatom is considered a heterocyclyl, regardless of the attachment(i.e., can be bound through a carbon atom or a heteroatom). Further, theterm heterocyclyl is intended to encompass any non-aromatic ringcontaining at least one heteroatom, which ring may be fused to an arylor heteroaryl ring, regardless of the attachment to the remainder of themolecule. As used herein, heterocyclyl has 2 to 20 ring atoms (i.e.,4-20 membered heterocyclyl), 2 to ring atoms (i.e., 4-12 memberedheterocyclyl), 4 to 10 ring atoms (i.e., 4-10 membered heterocyclyl), 4to 8 ring atoms (i.e., 4-8 membered heterocyclyl), or 4 to 6 ring carbonatoms (i.e., 4-6 membered heterocyclyl); having 1 to 5 ring heteroatoms,1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ringheteroatoms, or 1 ring heteroatom independently selected from nitrogen,sulfur or oxygen. A heterocyclyl may contain one or more oxo and/orthioxo groups. Examples of heterocyclyl groups include pyrrolidinyl,piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, azetidinyl,morpholinyl, thiomorpholinyl, 4-7 membered sultam, 4-7 membered cycliccarbamate, 4-7 membered cyclic carbonate, 4-7 membered cyclic sulfideand morpholinyl. As used herein, the term “bridged-heterocyclyl” refersto a four- to ten-membered cyclic moiety connected at two non-adjacentatoms of the heterocyclyl with one or more (e.g., 1 or 2) four- toten-membered cyclic moiety having at least one heteroatom where eachheteroatom is independently selected from nitrogen, oxygen, and sulfur.As used herein, bridged-heterocyclyl includes bicyclic and tricyclicring systems. Also used herein, the term “spiro-heterocyclyl” refers toa ring system in which a three- to ten-membered heterocyclyl has one ormore additional ring, wherein the one or more additional ring is three-to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, wherea single atom of the one or more additional ring is also an atom of thethree- to ten-membered heterocyclyl. Examples of the spiro-heterocyclylrings include bicyclic and tricyclic ring systems, such as2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl ringsinclude, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl,1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.As used herein, a bicyclic heterocyclyl group is a heterocyclyl groupattached at two points to another cyclic group, wherein the other cyclicgroup may itself be a heterocyclic group, or a carbocyclic group.

As used herein, the term “nitrogen or sulfur containing heterocyclyl”means a heterocyclyl moiety that contains at least one nitrogen atom orat least one sulfur atom, or both a nitrogen atom and a sulfur atomwithin the ring structure. It is to be understood that otherheteroatoms, including oxygen, may be present in addition to thenitrogen, sulfur, or combinations thereof. Examples of nitrogen orsulfur containing heterocyclyls include morpholinyl, thiomorpholinyl,thiazolyl, isothiazolyl, oxazolidinone 1,2 dithiolyl, piperidinyl,piperazinyl, and the like.

“Hydroxy” or “hydroxyl” refers to the group —OH. “Hydroxyalkyl” refersto an unbranched or branched alkyl group as defined above, wherein oneor more hydrogen atoms are replaced by a hydroxyl.

“Nitro” refers to the group —NO₂.

“Imino” refers to a group ═N—R^(y), or ═N—C(O)R^(y), wherein R^(y) isselected from the group consisting of hydrogen, alkyl, aryl, cyano,haloalkyl, or heteroaryl; each of which may be optionally substituted.

“Sulfoximine” or “sulfoximino” refers to a substituted or unsubstitutedmoiety of the general formula

wherein R^(y) is selected from the group consisting of hydrogen, alkyl,amino, aryl, cyano, haloalkyl, heterocyclyl, or heteroaryl; V and W areeach independently selected from a bond, alkyl, amino, aryl, haloalkyl,heterocyclyl or heteroaryl; each of which may be optionally substitutedand wherein R^(y) and V, R^(y) and W, and V and W together with theatoms to which they are attached may be joined together to form a ring.

“Sulfonyl” refers to the group —S(O)₂R, where R is a substituent, or adefined group.

“Alkylsulfonyl” refers to the group —S(O)₂R, where R is a substituent,or a defined group.

“Alkylsulfinyl” refers to the group —S(O)R, where R is a substituent, ora defined group.

“Thiocyanate” —SCN.

“Thiol” refers to the group —SR, where R is a substituent, or a definedgroup.

“Thioxo” or “thione” refer to the group (═S) or (S).

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.,arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen. “Optionally substituted” may be zero to the maximum number ofpossible substitutions, and each occurance is independent. When the term“substituted” is used, then that substitution is required to be made ata substitutable hydrogen atom of the indicated substituent. An optionalsubstitution may be the same or different from a (required)substitution.

When a moiety is “optionally substituted,” and reference is made to ageneral term, such as any “alkyl,” “alkenyl,” “alkynyl,” “haloalkyl,”“cycloalkyl,” “aryl”or “heteroaryl,” then the general term can refer toany antecedent specifically recited term, such as (C₁₋₃ alkyl), (C₄₋₆alkyl), —O(C₁₋₄ alkyl), (C₃₋₁₀ cycloalkyl), O—(C₃₋₁₀ cycloalkyl) and thelike. For example, “any aryl” includes both “aryl” and “—O(aryl) as wellas examples of aryl, such as phenyl or naphthyl and the like. Also, theterm “any heterocyclyl” includes both the terms “heterocyclyl” andO-(heterocyclyl),” as well as examples of heterocyclyls, such asoxetanyl, tetrahydropyranyl, morpholino, piperidinyl and the like. Inthe same manner, the term “any heteroaryl” includes the terms“heteroaryl” and “O-(heteroryl),” as well as specific heteroaryls, suchas pyridine and the like.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown, and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

Any formula or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogues” of compounds ofFormula I in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula I when administered to a mammal, particularly a human. See, forexample, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derivedfrom organic acids include acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluene-sulfonic acid, salicylic acid, and the like. Likewise,pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)3), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examples ofsuitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy,hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid,alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in some embodiments, the term “substituted alkyl” refers toan alkyl group having one or more substituents including hydroxyl, halo,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In otherembodiments, the one or more substituents may be further substitutedwith halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted. In other embodiments,the substituents may be further substituted with halo, alkyl, haloalkyl,alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each ofwhich is unsubstituted One skilled in the art will recognize thatsubstituents and other moieties of the compounds of the generic formulaherein should be selected in order to provide a compound which issufficiently stable to provide a pharmaceutically useful compound whichcan be formulated into an acceptably stable pharmaceutical composition.Compounds which have such stability are contemplated as falling withinthe scope of the present invention. It should be understood by oneskilled in the art that any combination of the definitions andsubstituents described above should not result in an inoperable speciesor compound.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

Combinations

Patients being treated by administration of the IRAK4 inhibitors of thedisclosure often exhibit diseases or conditions that benefit fromtreatment with other therapeutic agents. These diseases or conditionscan be of an inflammatory nature or can be related to cancer, metabolicdisorders, gastrointestinal disorders and the like. Thus, one aspect ofthe disclosure is a method of treating an inflammation related diseaseor condition, or a metabolic disorder, gastrointestinal disorder, orcancer and the like comprising administering a compound of the incombination with one or more compounds useful for the treatment of suchdiseases to a subject, particularly a human subject, in need thereof.

In some embodiments, a compound of the present disclosure isco-formulated with the additional one or more active ingredients. Insome embodiments, the other active ingredient is administered atapproximately the same time, in a separate dosage form. In someembodiments, the other active ingredient is administered sequentially,and may be administered at different times in relation to a compound ofthe present disclosure.

Combinations for Inflammatory Diseases and Conditions

For example, a compound of the present disclosure may be combined withone or more 5-Lipoxygenase inhibitors, Acetylcholinesterase inhibitors,Acetyl-CoA carboxylase (ACC) inhibitors, ACTH receptor agonists, Activinreceptor antagonists, Acyltransferase inhibitors, Adrenocorticotrophichormone ligands, AKT1 gene inhibitors, Alkaline phosphatase modulators,Alkaline phosphatase stimulators, Androgen receptor agonists,Apolipoprotein C3 antagonists, ASK1 kinase inhibitors, Bactericidalpermeability protein stimulators, Beta adrenoceptor antagonists,Beta-glucuronidase inhibitors, B-lymphocyte antigen CD20 inhibitors,Bradykinin receptor modulators, BTK kinase inhibitors, Calcineurininhibitors, Calcium channel inhibitors, Cannabinoid CB1 receptormodulators, Cannabinoid CB2 receptor modulators, Cannabinoid receptorantagonists, Cannabinoid receptor modulators, Caspase inhibitors,Cathepsin S inhibitors, CCN protein stimulators, CCR3 chemokineantagonists, CCR5 chemokine antagonists, CCR9 chemokine antagonists, CD3modulators, CD40 ligand inhibitors, CD40 ligand receptor antagonists,CD49b antagonists, CD49d antagonists, CD89 agonists, Cell adhesionmolecule inhibitors, Chemokine CXC ligand inhibitors, CHST15 geneinhibitors, Collagen modulators, CSF-1 agonists, CSF-1 antagonists,CXC10 chemokine ligand inhibitors, CXCR2 chemokine antagonists, CyclicGMP phosphodiesterase inhibitors, Cyclooxygenase 2 inhibitors,Cyclooxygenase inhibitors, Cyclooxygenase stimulators, Cytochrome P4503A4 inhibitors, Cytotoxic T-lymphocyte protein-4 stimulators,Dihydroceramide delta 4 desaturase inhibitors, Dihydroorotatedehydrogenase inhibitors, DNA polymerase inhibitors, DPP-4 inhibitors,EGFR family tyrosine kinase receptor modulators, Eosinophil peroxidaseinhibitors, Eotaxin ligand inhibitors, EP4 prostanoid receptor agonists,Epidermal growth factor agonists, Epidermal growth factor ligands,Estrogen receptor beta agonists, Factor XIII agonists, FGF-10 ligands,FGF2 receptor agonists, Fractalkine ligand inhibitors, Free fatty acidreceptor 2 antagonists, FXR agonists, GATA 3 transcription factorinhibitors, Glucagon-like peptide 1 agonists , Glucagon-like peptide 2agonists, Glucocorticoid agonists, GM-CSF receptor agonists, G-proteincoupled receptor 84 antagonists, Guanylate cyclase receptor agonists,Histamine H2 receptor antagonists, Histone acetyltransferase inhibitors,Histone deacetylase inhibitors, HLA class II antigen modulators,Hydrolase inhibitors, HSD171313 inhibitors, ICAM1 gene inhibitors,ICAM-1 inhibitors, IL1 gene inhibitors, IL-10 agonists, IL10 genestimulators, IL-11 agonists, IL-12 antagonists, IL12 gene inhibitors,IL-13 antagonists, IL-17 antagonists, IL-2 antagonists, IL-2 receptoralpha subunit inhibitors, IL-21 antagonists, IL-23 antagonists, IL-6antagonists, IL6 gene inhibitors, IL-6 receptor modulators, IL-7antagonists, IL-8 antagonists, Immunoglobulin G1 agonists,Immunoglobulin G2 modulators, Inosine monophosphate dehydrogenaseinhibitors, Insulin sensitizers, Integrin alpha-4/beta-1 antagonists,Integrin alpha-4/beta-7 antagonists, Integrin alpha-E antagonists,Integrin antagonists, Integrin beta-7 antagonists, Interferon betaligands, Interleukin 17E ligand inhibitors, Interleukin ligandinhibitors, Interleukin receptor 17A antagonists, Interleukin receptor17B antagonists, Interleukin-1 beta ligands, Interleukin-1 beta ligandmodulators, Interleukin-6 ligand inhibitors, JAK tyrosine kinaseinhibitors, Jakl tyrosine kinase inhibitors, JAK2 gene inhibitors, Jak3tyrosine kinase inhibitors, Jun N terminal kinase inhibitors, LanC likeprotein 2 modulators, Leukotriene BLT receptor antagonists, Lipoxygenasemodulators, L-Selectin antagonists, MAdCAM inhibitors, Matrixmetalloprotease inhibitors, Matrix metalloprotease modulators,Melanocortin agonists, Membrane copper amine oxidase inhibitors,Metalloprotease-2 inhibitors, Metalloprotease-9 inhibitors, MIP 3 alphaligand inhibitors, Mitochondrial 10 kDa heat shock protein stimulators,Monocyte differentiation antigen CD14 inhibitors, mTOR inhibitors, Mucinstimulators, NAD-dependent deacetylase sirtuin-1 stimulators,Natriuretic peptide receptor C agonists, Neuregulin-4 ligands, Nicotinicacetylcholine receptor agonists, Nicotinic ACh receptor alpha 4 subunitmodulators, Nicotinic ACh receptor alpha 7 subunit stimulators,Nicotinic ACh receptor beta 2 subunit modulators, NK1 receptorantagonists, NKG2 D activating NK receptor antagonists, Nuclear factorkappa B inhibitors, Opioid growth factor receptor agonists, Opioidreceptor antagonists, Opioid receptor delta antagonists, Oxidoreductaseinhibitors, P2X7 purinoceptor agonists, p38 MAP kinase inhibitors, PARPinhibitors, PDE 4 inhibitors, PDGF receptor agonists, Phagocytosisstimulating peptide modulators, Phospho MurNAc pentapeptide transferaseinhibitors, Phospholipase A2 inhibitors, Platelet activating factorreceptor antagonists, Potassium channel inhibitors, PPAR alpha agonists,PPAR delta agonists, PPAR gamma agonists, Protein CYR61 stimulators,Protein fimH inhibitors, Protein kinase C alpha inhibitors, Proteinkinase C beta inhibitors, Protein kinase C delta inhibitors, Proteinkinase C epsilon inhibitors, Protein kinase C eta inhibitors, Proteinkinase C theta inhibitors, Protein kinase G inhibitors, Protein kinaseinhibitors, P-selectin glycoprotein ligand-1 inhibitors, PurH purinebiosynthesis protein inhibitors, Retinoic acid receptor alpha agonists,Retinoic acid receptor beta agonists, Retinoid receptor agonists, RNApolymerase inhibitors, SMAD-7 inhibitors, Sodium channel inhibitors,Somatostatin receptor agonists, Sphingosine 1 phosphate phosphatase 1stimulators, Sphingosine 1 phosphate phosphatase modulators, Sphingosinekinase 1 inhibitors, Sphingosine kinase 2 inhibitors,Sphingosine-1-phosphate receptor-1 agonists, Sphingosine-1-phosphatereceptor-1 antagonists, Sphingosine-1-phosphate receptor-1 modulators,Sphingosine-1-phosphate receptor-5 modulators, STAT3 gene inhibitors,STAT-3 inhibitors, STAT-4 inhibitors, Stem cell antigen-1 inhibitors,Superoxide dismutase modulators, Superoxide dismutase stimulators, SYKkinase inhibitors, T cell surface glycoprotein CD28 inhibitors, TGF beta1 ligand inhibitors, Thymulin agonists, THR-β agonists, TLR-2antagonists, TLR-4 antagonists, TLR-9 agonists, TNF alpha ligandinhibitors, TNF alpha ligand modulators, TNF antagonists, TPL2 kinaseinhibitors, Trefoil factor modulators, Tryptase inhibitors, Tryptophan5-hydroxylase inhibitors, Tumor necrosis factor 14 ligand modulators,TYK2 kinase inhibitors, Type I TNF receptor antagonists, Type II TNFreceptor modulators, Unspecified growth factor receptor modulators,Vanilloid VR1 agonists, Vitamin D3 receptor agonists, Zonulininhibitors, abatacept; acemannan; adalimumab; DCCT-10; apremilast;AST-120; balsalazide; balsalazide sodium; basiliximab; beclomethasonedipropionate; budesonide; D-9421; budesonide MMX; catridecacog;certolizumab pegol; Clostridium butyricum; etanercept; fingolimod;glatiramer acetate; golimumab; infliximab; infliximab biosimilar;infliximab follow-on biologic; interferon beta-1a; lenalidomide;mesalazine; GED-0001; AJG-501; metenkefalin acetate with tridecactideacetat, mycophenolate mofetil; naltrexone; natalizumab; nitazoxanide;olsalazine; oprelvekin; propionyl-L-carnitine; recombinant interferonbeta-1a; remestemcel-L; rifaximin; rituximab; ropivacaine;rosiglitazone; sargramostim; secukinumab; SPD-480; tacrolimus;tamibarotene; teduglutide; thalidomide; tocilizumab; RO-4877533;tofacitinib; CP-690550; Trichuris suis ova; ASP-1002; ustekinumab;valganciclovir; vedolizumab; zileuton; anti-CD3 imaging agent (antibodyfragment, cancer/autoimmune disease), ImaginAb; AVX-470; ciclosporin;CXCR1/2 ligands mAb (immunology), Eli Lilly; FFP-102; GSK-3050002;INN-108; IR-777; SGM-1019; peg-ilodecakin; PF-06480605; PF-06651600;SER-287; Syn-1002; Thetanix; tolerogenic dendritic cell therapyTOP-1288; VBY-036; VBY-129; 946414-98-8; BMS-936557; 99mTc-annexinV-128; ABC-294640; abrilumab; Alequel; AMG-139; amiselimod; APD-334;ASP-3291; beclomethasone dipropionate; bertilimumab; ciclosporin;clazakizumab; DLX-105; dolcanatide; E-6011; ETX-201; FFP-104;filgotinib; foralumab; GED-0507-34-Levo; givinostat; GLPG-0974;GLPG-1205; iberogast N (ulcerative colitis), Bayer; BAY98-7410; INV-103;JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate;CB-01-05-MMX; LY-3074828; mesalamine with N-acetylcysteine; midismase;molgramostim follow on biologic with fosfomycin with carbapenem ,Reponex; multipotent adult progenitor cell therapy (ischemia/cerebralpalsy), Athersys/Healios; NN-8828; olokizumab; OvaSave; P-28-GST;PDA-002; PF-4236921; PF-547659; prednisolone; PUR-0110; QBECO; RBX-2660;repurposed naltrexone; JKB-122; SB-012; sotrastaurin; STNM-01; TAK-114;tetomilast; Debio-0512; TRK-170; TRX-318; vatelizumab; VB-201; ZP-1848;zucapsaicin; ABT-494; alicaforsen; Ampion; BI-655066; briakinumab;cannabidiol; carotegast methyl; cobitolimod; dexamethasone sodiumphosphate; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02;mesalazine; metronidazole mongersen; ocrelizumab; ozanimod; peficitinib;RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod;plecanatide; telotristat etiprate; infliximab biosimilar, SamsungBioepis; AZD-058;and rifabutin with clarithromycin and further withclofazimine.

Also, the following non-exhaustive list of classes of compounds andcompounds may be combined with a compound of the present disclosure:5-Lipoxygenase inhibitors, such as zileuton, etalocibm FPL-64170,E-3040, and BU-4601A; Acetylcholinesterase inhibitors, such as BL-7040;ACTH receptor agonists, such as metenkefalin acetate with tridecactideacetate, and FAR-404; Activin receptor antagonists such as follistatin;Acyltransferase inhibitors such as AZD-0585; Adrenocorticotrophichormone ligands, such as metenkefalin acetate with tridecactide acetate,and FAR-404; AKT1 gene inhibitors, such as vidofludimus; Alkalinephosphatase modulators such as recombinant human alkaline phosphatase(oral, ulcerative colitis), AM-Pharma; Alkaline phosphatase stimulatorssuch as bovine alkaline phosphatase; Androgen receptor agonists, such asPB-005; Apolipoprotein C3 antagonists, such as AZD-0585; Bactericidalpermeability protein stimulators, such as opebacan; Beta adrenoceptorantagonists, such as NM-001; Beta-glucuronidase inhibitors, such asKD-018; B-lymphocyte antigen CD20 inhibitors, such as ocrelizumab,rituximab; Bradykinin receptor modulators, such as givinostat;Calcineurin inhibitors, such as tacrolimus, ciclosporin; Calcium channelinhibitors, such as clotrimazole; Cannabinoid CB1 receptor modulators,such as GWP42003-P, cannabidiol; Cannabinoid CB2 receptor modulators,such as GWP42003-P, cannabidiol; Cannabinoid receptor antagonists, suchas fingolimod; Cannabinoid receptor modulators, such as GWP42003-P,cannabidiol; Cathepsin S inhibitors, such as VBY-129, VBY-036; CCNprotein stimulators, such as CSA-13; CCR3 chemokine antagonists, such asbertilimumab; CCR5 chemokine antagonists, such as HGS-1025; CCR9chemokine antagonists, such as MLN-3126, vercirnon, CCX-025; CD3modulators, such as visilizumab; CD40 ligand inhibitors, such asFFP-104; CD40 ligand receptor antagonists, such as FFP-104, FFP-102,toralizumab; CD49b antagonists, such as vatelizumab; CD49d antagonists,such as ELND-004; CD89 agonists, such as HF-1020; Cell adhesion moleculeinhibitors, such as natalizumab, alicaforsen (intravenous), ASP-2002,ISIS-2302; Chemokine CXC ligand inhibitors, such as CXCR1/2 ligands mAb(immunology), Eli Lilly; CHST15 gene inhibitors, such as STNM-01;Collagen modulators, such as adipose-derived stem cell therapy (CelutionSystem), Cytori, DCCT-10; CSF-1 agonists, such as sargramostim,molgramostim follow on biologic with fosfomycin with carbapenem(intraintestinal, Crohn's disease), Reponex; CSF-1 antagonists, such asJNJ-40346527; CXC10 chemokine ligand inhibitors, such as 946414-98-8,BMS-936557; CXCR2 chemokine antagonists, such as elubrixin; Cyclic GMPphosphodiesterase inhibitors, such as CEL-031; Cyclooxygenase 2inhibitors, such as P-54; Cyclooxygenase inhibitors, such as mesalazine,4-aminosalicylate sodium, AJG-501, AGI-022; Cyclooxygenase stimulators,such as nicotine polacrilex; Cytochrome P450 3A4 inhibitors, such asKD-018; Cytotoxic T-lymphocyte protein-4 stimulators, such as abatacept;Dihydroceramide delta 4 desaturase inhibitors, such as ABC-294640;Dihydroorotate dehydrogenase inhibitors, such as vidofludimus; DNApolymerase inhibitors, such as valganciclovir; EGFR family tyrosinekinase receptor modulators, such as neuregulin 4 (Crohn'sdisease/ulcerative colitis/necrotizing enterocolitis), AvexegenTherapeutics/Children's Hospital of Los Angeles; Eosinophil peroxidaseinhibitors, such as AWEPOPD-01, AWEPO-003; Eotaxin ligand inhibitors,such as bertilimumab; EP4 prostanoid receptor agonists, such as KAG-308;Epidermal growth factor agonists, such as heparin-EGF-like factor, SciosNova; Epidermal growth factor ligands, such as Hebervis; Estrogenreceptor beta agonists, such as prinaberel; Factor XIII agonists, suchas catridecacog; FGF-10 ligands, such as repifermin; FGF2 receptoragonists, such as F2A; Fractalkine ligand inhibitors, such as E-6011;Free fatty acid receptor 2 antagonists, such as GLPG-0974; GATA 3transcription factor inhibitors, such as SB-012; Glucagon-like peptide 2agonists, such as teduglutide, ZP-1848, NB-1002; Glucocorticoidagonists, such as budesonide, beclomethasone dipropionate, dexamethasonesodium phosphate, AJG-511, DOR-201, D-9421-C; GM-CSF receptor agonists,such as sargramostim, molgramostim follow on biologic with fosfomycinwith carbapenem (intraintestinal, Crohn's disease), Reponex; G-proteincoupled receptor 84 antagonists, such as GLPG-1205; Guanylate cyclasereceptor agonists, such as dolcanatide, SP-333; Histamine H2 receptorantagonists, such as bismuth, Medeva; Histone acetyltransferaseinhibitors, such as TIP60 inhibitors (ulcerative colitis/inflammatorybowel disease/autoimmune diseases), University of Pennsylvania; Histonedeacetylase inhibitors, such as givinostat; HLA class II antigenmodulators, such as HLA class II protein modulators (Crohns disease),Nextera AS; Hydrolase inhibitors, such as SC-56938; ICAM1 geneinhibitors, such as alicaforsen; ICAM-1 inhibitors, such as alicaforsen(intravenous), ISIS-2302; IL1 gene inhibitors, such as PLR-14; IL-10agonists, such as peg-ilodecakin, AM-0010; IL10 gene stimulators, suchas gene therapy (IL-10), Imperial College; IL-11 agonists, such asoprelvekin, YM-294; IL-12 antagonists, such as ustekinumab, briakinumab,apilimod; IL12 gene inhibitors, such as RDP-58; IL-13 antagonists, suchas tralokinumab, anrukinzumab; IL-17 antagonists, such as secukinumab,vidofludimus; IL-2 antagonists, such as daclizumab; IL-2 receptor alphasubunit inhibitors, such as basiliximab, daclizumab, BSX-003,Ro-34-7375; IL-21 antagonists, such as NN-8828, ATR-107; IL-23antagonists, such as tildrakizumab, ustekinumab, BI-655066, AMG-139,briakinumab, LY-3074828, apilimod; IL-6 antagonists, such astocilizumab, clazakizumab, olokizumab, HMPL-004, AMG-220, FM-101; IL6gene inhibitors, such as YSIL6-T-PS; IL-6 receptor modulators, such astocilizumab; IL-7 antagonists, such as interleukin-7 receptor modulators(ulcerative colitis/T-cell acute lymphoblastic leukaemia), Effimune;IL-8 antagonists, such as elubrixin, clotrimazole; Immunoglobulin G1agonists, such as HF-1020; Immunoglobulin G2 modulators, such asPF-547659; Inosine monophosphate dehydrogenase inhibitors, such asmycophenolate mofetil; Insulin sensitizers, such as elafibranor,rosiglitazone, HE-3286, EGS-21; Integrin alpha-4/beta-1 antagonists,such as natalizumab, TRK-170, firategrast; Integrin alpha-4/beta-7antagonists, such as etrolizumab, vedolizumab, abrilumab, carotegastmethyl, TRK-170, firategrast; Integrin alpha-E antagonists, such asetrolizumab; Integrin antagonists, such as vatelizumab, ASP-2002;Integrin beta-7 antagonists, such as etrolizumab; Interferon betaligands, such as interferon beta-1a, recombinant interferon beta-1a,Serono; Interleukin 17E ligand inhibitors, such as anti-IL-17BRhumanized antibody (lung fibrosis/asthma/ulcerative colitis), MedicalResearch Council Technology; Interleukin ligand inhibitors, such asHE-3286; Interleukin receptor 17A antagonists, such as brodalumab;Interleukin receptor 17B antagonists, such as anti-IL-17BR humanizedantibody (lung fibrosis/asthma/ulcerative colitis), Medical ResearchCouncil Technology; Interleukin-1 beta ligands, such as K(D)PT,PUR-0110, HMPL-004; Interleukin-1 beta ligand modulators, such asPUR-0110, HMPL-004; Interleukin-6 ligand inhibitors, such as PF-4236921;JAK tyrosine kinase inhibitors, such as tofacitinib, peficitinib; Jak1tyrosine kinase inhibitors, such as ABT-494, tofacitinib, filgotinib,peficitinib, GLPG-0555, solcitinib; JAK2 gene inhibitors, such asvidofludimus; Jak3 tyrosine kinase inhibitors, such as tofacitinib,peficitinib; Jun N terminal kinase inhibitors, such as semapimod; LanClike protein 2 modulators, such as BT-11; Leukotriene BLT receptorantagonists, such as ONO-4057, etalocib, SC-53228, SC-52798;Lipoxygenase modulators, such as mesalazine; L-Selectin antagonists,such as BNP-001; MAdCAM inhibitors, such as vedolizumab, PF-547659;Matrix metalloprotease inhibitors, such as D-5410; Matrixmetalloprotease modulators, such as D-5410; Melanocortin agonists, suchas ASP-3291; Membrane copper amine oxidase inhibitors, such asvepalimomab; Metalloprotease-2 inhibitors, such as KD-018, RWJ-68354;Metalloprotease-9 inhibitors, such as GS-5745; MIP 3 alpha ligandinhibitors, such as GSK-3050002; Mitochondrial 10 kDa heat shock proteinstimulators, such as INV-103; Monocyte differentiation antigen CD14inhibitors, such as CD14 anti-inflammatory, Cornell; mTOR inhibitors,such as P-2281; Mucin stimulators, such as rebamipide; NAD-dependentdeacetylase sirtuin-1 stimulators, such as SRT-2104; Natriuretic peptidereceptor C agonists, such as plecanatide; Neuregulin-4 ligands, such asneuregulin 4 (Crohn's disease/ulcerative colitis/necrotizingenterocolitis), Avexegen Therapeutics/Children's Hospital of LosAngeles; Nicotinic acetylcholine receptor agonists, such as TC-2403,nicotine polacrilex, nicotine; Nicotinic ACh receptor alpha 4 subunitmodulators, such as TC-2403; Nicotinic ACh receptor alpha 7 subunitstimulators, such as GTS-21; Nicotinic ACh receptor beta 2 subunitmodulators, such as TC-2403; NK1 receptor antagonists, such as KD-018,nolpitantium besilate; NKG2 D activating NK receptor antagonists, suchas NNC-0142-002; Nuclear factor kappa B inhibitors, such as KD-018,cobitolimod, CSA-13, HE-3286, HMPL-004, Avrina, mesalamine withN-acetylcysteine , P-54; Opioid growth factor receptor agonists, such asmetenkefalin acetate with tridecactide acetate, FAR-404; Opioid receptorantagonists, such as naltrexone, IRT-103; Opioid receptor deltaantagonists, such as KD-018; Oxidoreductase inhibitors, such asolsalazine; P2X7 purinoceptor agonists, such as givinostat; p38 MAPkinase inhibitors, such as RDP-58, doramapimod, semapimod, RWJ-68354;PARP inhibitors, such as EB-47, INO-1003; PDE 4 inhibitors, such asapremilast, tetomilast, CC-1088; PDGF receptor agonists, such asoprelvekin, YM-294; Phagocytosis stimulating peptide modulators, such as99mTc-RP-128; Phospho MurNAc pentapeptide transferase inhibitors, suchas SQ-641; Phospholipase A2 inhibitors, such as varespladib methyl;Platelet activating factor receptor antagonists, such as dersalazinesodium; Potassium channel inhibitors, such as clotrimazole; PPAR alphaagonists, such as elafibranor (GFT-1007); PPAR delta agonists, such aselafibranor (GFT-1007); PPAR gamma agonists, such as rosiglitazone,GED-0507-34-Levo, etalocib; Protein CYR61 stimulators, such as CSA-13;Protein fimH inhibitors, such as EB-8018; Protein kinase C alphainhibitors, such as sotrastaurin (AEB-071); Protein kinase C betainhibitors, such as sotrastaurin (AEB-071); Protein kinase C deltainhibitors, such as sotrastaurin (AEB-071); Protein kinase C epsiloninhibitors, such as sotrastaurin (AEB-071); Protein kinase C etainhibitors, such as sotrastaurin (AEB-071); Protein kinase C thetainhibitors, such as sotrastaurin (AEB-071); Protein kinase G inhibitors,such as CEL-031; Protein kinase inhibitors, such as TOP-1288; P-selectinglycoprotein ligand-1 inhibitors, such as SEL-K2; PurH purinebiosynthesis protein inhibitors, such as mycophenolate mofetil; Retinoicacid receptor alpha agonists, such as tamibarotene; Retinoic acidreceptor beta agonists, such as tamibarotene; Retinoid receptoragonists, such as tamibarotene; RNA polymerase inhibitors, such asrifaximin; SMAD-7 inhibitors, such as mongersen (GED-0301); Sodiumchannel inhibitors, such as ropivacaine; Somatostatin receptor agonists,such as vapreotide; Sphingosine 1 phosphate phosphatase 1 stimulators,such as APD-334; Sphingosine 1 phosphate phosphatase modulators, such asS11³ modulators (oral, multiple sclerosis/ulcerative colitis/rheumatoidarthritis), Akaal Pharma; Sphingosine kinase 1 inhibitors, such asABC-294640; Sphingosine kinase 2 inhibitors, such as ABC-294640;Sphingosine-1-phosphate receptor-1 agonists, such as ozanimod(RPC-1063), KRP-203; Sphingosine-1-phosphate receptor-1 antagonists,such as amiselimod (MT-1303); Sphingosine-1-phosphate receptor-1modulators, such as fingolimod (FTY-720), ozanimod (RPC-1063),amiselimod (MT-1303); Sphingosine-1-phosphate receptor-5 modulators,such as ozanimod; STAT3 gene inhibitors, such as vidofludimus; STAT-3inhibitors, such as TAK-114; STAT-4 inhibitors, such as STAT-4 antisenseoligonucleotide (Crohns disease/colitis), NIAID; Stem cell antigen-1inhibitors, such as Ampion, DMI-9523; Superoxide dismutase modulators,such as midismase, LT-0011; Superoxide dismutase stimulators, such assuperoxide dismutase; T cell surface glycoprotein CD28 inhibitors, suchas abatacept; TGF beta 1 ligand inhibitors, such as mongersen, GED-0301;Thymulin agonists, such as Syn-1002; TLR-2 antagonists, such as VB-201;TLR-4 antagonists, such as JKB-122, VB-201; TLR-9 agonists, such asBL-7040, cobitolimod; TNF alpha ligand inhibitors, such as adalimumab,certolizumab pegol, infliximab biosimilar, infliximab, golimumab,ISIS-104838, CSA-13, DLX-105, adalimumab biosimilar, dersalazine sodium,Debio-0512, HMPL-004, DLX-105, infliximab follow-on biologic, AZD-9773,CYT-020-TNFQb, DOM-0200; TNF alpha ligand modulators, such as PUR-0110,CDP-571; TNF antagonists, such as etanercept, certolizumab pegol,AVX-470, onercept; Trefoil factor modulators, such as AG-012; Tryptaseinhibitors, such as APC-2059; Tryptophan 5-hydroxylase inhibitors, suchas telotristat etiprate; Tumor necrosis factor 14 ligand modulators,such as SAR-252067; Type I TNF receptor antagonists, such as DOM-0100;Type II TNF receptor modulators, such as etanercept; Unspecified growthfactor receptor modulators, such as AP-005; Vanilloid VR1 agonists, suchas zucapsaicin; Vitamin D3 receptor agonists, such as calcitriol; andZonulin inhibitors, such as larazotide acetate, AT-1001.

Also, the following non-exhaustive list of classes of compounds andcompounds may be combined with a compound of the present disclosure:14-3-3 protein eta inhibitors, 5-Lipoxygenase inhibitors, Abl tyrosinekinase inhibitors, ACTH receptor agonists, Adenosine A3 receptoragonists, Adenosine deaminase inhibitors, ADP ribosyl cyclase-1modulators, ADP ribosylation factor 6 inhibitors, Adrenocorticotrophichormone ligands, Aggrecanase-2 inhibitors, Albumin modulators, AP1transcription factor inhibitors, Basigin inhibitors, Bcr proteininhibitors, B-lymphocyte antigen CD19 inhibitors, B-lymphocyte antigenCD20 inhibitors, B-lymphocyte antigen CD20 modulators, B-lymphocytestimulator ligand inhibitors, Bradykinin receptor modulators, BRAF geneinhibitors, Branched amino acid aminotransferase 1 inhibitors,Bromodomain containing protein inhibitors, Btk tyrosine kinaseinhibitors, Cadherin-11 antagonists, Calcineurin inhibitors, Calciumchannel inhibitors, Carbonic anhydrase inhibitors, Cathepsin Kinhibitors, Cathepsin S inhibitors, CCR1 chemokine antagonists, CCR2chemokine antagonists, CCR3 gene modulators, CCR5 chemokine antagonists,CD126 antagonists, CD29 modulators, CD3 modulators, CD39 agonists, CD4agonists, CD4 antagonists, CD40 ligand inhibitors, CD40 ligand receptorantagonists, CD40 ligand receptor modulators, CD52 antagonists, CD73agonists, CD79b modulators, CD80 antagonists, CD86 antagonists, CD95antagonists, Cell adhesion molecule inhibitors, Choline kinaseinhibitors, Clusterin stimulators, Complement C5 factor inhibitors,Complement Factor stimulators, C-reactive protein inhibitors, CSF-1antagonists, CXC10 chemokine ligand inhibitors, CXCR4 chemokineantagonists, Cyclin-dependent kinase inhibitor 1 inhibitors,Cyclin-dependent kinase-2 inhibitors, Cyclin-dependent kinase-4inhibitors, Cyclin-dependent kinase-5 inhibitors, Cyclin-dependentkinase-6 inhibitors, Cyclin-dependent kinase-7 inhibitors,Cyclin-dependent kinase-9 inhibitors, Cyclooxygenase 2 inhibitors,Cyclooxygenase 2 modulators, Cyclooxygenase inhibitors, Cytosolicphospholipase A2 inhibitors, Cytotoxic T-lymphocyte protein-4modulators, Cytotoxic T-lymphocyte protein-4 stimulators, DHFRinhibitors, Diamine acetyltransferase inhibitors, Dihydroorotatedehydrogenase inhibitors, Elongation factor 2 inhibitors, Eotaxin 2ligand inhibitors, EP4 prostanoid receptor antagonists, Erythropoietinreceptor agonists, Fas ligands, FGF-2 ligand inhibitors, FK506 bindingprotein-12 modulators, Folate antagonists, Folate receptor agonists,Folate receptor beta antagonists, Folate receptor modulators,Fractalkine ligand inhibitors, Fyn tyrosine kinase inhibitors, G proteincoupled receptor 15 antagonists, GABA A receptor modulators,Glucocorticoid agonists, Glucocorticoid antagonists, Glucocorticoidinduced leucine zipper stimulators, GM-CSF ligand inhibitors, GM-CSFreceptor antagonists, GM-CSF receptor modulators, Growth regulatedprotein alpha ligand inhibitors, Hwith Kwith ATPase inhibitors,Histamine H4 receptor antagonists, Histone deacetylase inhibitors,Histone deacetylase-6 inhibitors, HIV-1 gp120 protein inhibitors, HLAclass II antigen DQ-2 alpha modulators, HLA class II antigen inhibitors,HLA class II antigen modulators, Hsp 70 family inhibitors, Hypoxiainducible factor-1 inhibitors, IFNB gene stimulators, I-kappa B kinasebeta inhibitors, I-kappa B kinase inhibitors, IL-1 antagonists, IL-10agonists, IL-11 agonists, IL-12 antagonists, IL-15 antagonists, IL-17antagonists, IL-17 receptor modulators, IL-2 agonists, IL-2 antagonists,IL-21 antagonists, IL-23 antagonists, IL-3 antagonists, IL-4 agonists,IL-6 antagonists, IL-6 receptor modulators, Immunoglobulin antagonists,Immunoglobulin G1 agonists, Immunoglobulin G1 antagonists,Immunoglobulin G1 modulators, Immunoglobulin G2 antagonists,Immunoglobulin G2 modulators, Immunoglobulin gamma Fc receptor IImodulators, Immunoglobulin gamma Fc receptor IIB antagonists,Immunoglobulin kappa modulators, Immunoglobulin M antagonists, Induciblenitric oxide synthase inhibitors, Inosine monophosphate dehydrogenaseinhibitors, Insulin sensitizers, Integrin alpha-1/beta-1 antagonists,Integrin alpha-4/beta-1 antagonists, Integrin antagonists, Interferonbeta ligands, Interferon gamma ligands, Interleukin 17A ligandinhibitors, Interleukin 17F ligand inhibitors, Interleukin 23Ainhibitors, Interleukin ligands, Interleukin receptor 17A antagonists,Interleukin-1 beta ligand inhibitors, Interleukin-10 ligands,Interleukin-2 ligands, Interleukin-4 ligands, Interleukin-6 ligandinhibitors, Itk tyrosine kinase inhibitors, JAK tyrosine kinaseinhibitors, Jakl tyrosine kinase inhibitors, Jak2 tyrosine kinaseinhibitors, JAK3 gene inhibitors, Jak3 tyrosine kinase inhibitors, Jun Nterminal kinase inhibitors, KCNA voltage-gated potassium channel-3modulators, Kelch like ECH associated protein 1 modulators, Kit tyrosinekinase inhibitors, LanC like protein 2 modulators, LITAF geneinhibitors, Lymphocyte function antigen-3 receptor antagonists, Lyntyrosine kinase inhibitors, Macrophage mannose receptor 1 modulators,MAdCAM inhibitors, MAP kinase modulators, MAP3K2 gene inhibitors,MAPKAPK5 inhibitors, Matrix metalloprotease inhibitors, MCL1 geneinhibitors, MEK protein kinase inhibitors, MEK-1 protein kinaseinhibitors, MEK-2 protein kinase inhibitors, Membrane copper amineoxidase inhibitors, Metalloprotease-2 inhibitors, Metalloprotease-9inhibitors, Midkine ligand inhibitors, Mitochondrial 10 kDa heat shockprotein stimulators, mTOR complex 1 inhibitors, mTOR inhibitors, NAD ADPribosyltransferase stimulators, NAMPT gene inhibitors, NF kappa Binhibitor stimulators, NFAT gene inhibitors, NFE2L2 gene stimulators,Nicotinic acetylcholine receptor antagonists, NK cell receptormodulators, NKG2 A B activating NK receptor antagonists, NKG2 Dactivating NK receptor antagonists, Nuclear erythroid 2-related factor 2stimulators, Nuclear factor kappa B inhibitors, Nuclear factor kappa Bmodulators, Nuclear factor kappa B p105 inhibitors, Opioid growth factorreceptor agonists, Opioid receptor delta antagonists, Osteoclastdifferentiation factor antagonists, Osteoclast differentiation factorligand inhibitors, Oxidoreductase inhibitors, P2X7 purinoceptoragonists, p38 MAP kinase alpha inhibitors, p38 MAP kinase inhibitors,PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor agonists, PDGFreceptor antagonists, PDGF-B ligand inhibitors, PERK gene inhibitors,Phosphoinositide-3 kinase delta inhibitors, Phosphoinositide-3 kinasegamma inhibitors, Phospholipase A2 inhibitors, Platelet activatingfactor receptor antagonists, PPAR gamma agonists, Programmed cell deathprotein 1 modulators, Prostaglandin D synthase stimulators, Proteinarginine deiminase inhibitors, Protein tyrosine kinase inhibitors, PurHpurine biosynthesis protein inhibitors, Rho associated protein kinase 2inhibitors, Seprase inhibitors, Signal transducer CD24 modulators,Signal transduction inhibitors, Sodium glucose transporter-2 inhibitors,Sphingosine 1 phosphate phosphatase modulators, STAT3 gene inhibitors,Superoxide dismutase stimulators, SYK family tyrosine kinase inhibitors,Syk tyrosine kinase inhibitors, Syndecan-1 inhibitors, T cell receptorantagonists, T cell receptor modulators, T cell surface glycoproteinCD28 inhibitors, T cell surface glycoprotein CD28 stimulators, TAK1binding protein modulators, Talin modulators, T-cell differentiationantigen CD6 inhibitors, T-cell surface glycoprotein CD8 inhibitors,Tenascin modulators, TGF beta agonists, Thymulin agonists, TLR-2antagonists, TLR-4 antagonists, TLR-9 antagonists, TNF alpha ligandinhibitors, TNF alpha ligand modulators, TNF antagonists, TNF geneinhibitors, TNF receptor modulators, TNFSF11 gene inhibitors,Transcription factor p65 inhibitors, Transcription factor RelBinhibitors, Transferrin modulators, Tumor necrosis factor 13C receptorantagonists, Tumor necrosis factor 15 ligand inhibitors, Tumor necrosisfactor ligand 13 inhibitors, Tumor necrosis factor ligand inhibitors,Type I IL-1 receptor antagonists, Type I TNF receptor antagonists, TypeII TNF receptor modulators, Unspecified GPCR agonists, VEGF receptorantagonists, VEGF-2 receptor antagonists, VEGF-2 receptor modulators,VEGF-B ligand inhibitors, X-linked inhibitor of apoptosis proteininhibitors, Zap70 tyrosine kinase inhibitors, 99mTc labelled annexinV-128, abatacept, abatacept biosimilar, ABBV-257, ABT-122, ABT-494,acalabrutinib, aceclofenac, actarit, MS-392, adalimumab, adalimumabbiosimilar, adalimumab follow-on biologic, AK-106, ALX-0061,aminopterin, anakinra, anakinra biosimilar, anakinra follow-on biologic,ARG-301, ASLAN-003, ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064,bimekizumab, BiP (rheumatoid arthritis), Kings College London, BLHP-006,blisibimod, BMS-986104, BMS-986142, ABBV-105, BTT-1023, canakinumab,Cartistem, CCX-354, CD24-IgFc, celecoxib, cerdulatinib, certolizumabpegol, CF-101, CFZ-533, CHR-5154, cibinetide, ciclosporin, clazakizumab,CNTO-6785, corticotropin, Mallinckrodt, CR-6086, CreaVax-RA, CWG-92,CWG-940, Cx-611, DE-098, deflazacort, Rheumavax, denosumab, diacerein,diclofenac, E-6011, eicosapentaenoic acid monoglycerides, etanercept,etanercept biosimilar, etanercept follow-on biologic, etodolac,etoricoxib, filgotinib, fosdagrocorat, gerilimzumab, ginsenoside C-K,givinostat, goat polyclonal antibodies, golimumab, GS-5745, GS-9876,GSK-3196165, HM-71224, HMPL-523, hyaluronate sodium, IB-RA (injectable,rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoidarthritis), Innobioscience, iguratimod, IMD-2560, imidazole salicylate,infliximab, infliximab biobetter, infliximab biosimilar, INSIX RA,interferon gamma follow-on biologic, interleukin-2 (injectable),interleukin-2 follow-on biologic, INV-103, IR-501, itolizumab,JNJ-40346527, Ka Shu Ning, KD-025, ketoprofen with omeprazole,leflunomide, lenzilumab, LLDT-8, lumiracoxib, LY-3090106, masitinib,mavrilimumab, MBS-2320, MEDI-5117, meloxicam, methotrexate, MGD-010,misoprostol with diclofenac, MM-A01-01, monalizumab, MORAb-022,MPC-300-IV, MRC-375, nabumetone, namilumab, naproxen with esomeprazole,naproxen with esomeprazole strontium, ocaratuzumab, ofatumumab, OHR-118, olokizumab, OM-89, once-daily naproxen (oral controlled release,pain), Alvogen, ONO-4059, Oralgam, ozoralizumab, peficitinib,pelubiprofen, PF-06687234, piperidone hydrochloridum, piroxicam,prednisolone, prednisone, Prosorba, PRT-2607, PRTX-100, PRX-167700,QBSAU, rabeximod, RCT-18, recombinant human CD22 monoclonal antibody (ivinfusion), Lonn Ryonn Pharma/SinoMab Bioscience (Shenzhen), recombinanthuman interleukin-1 receptor antagonist (rheumatoid arthritis), ShanghaiFudan-Zhangjiang Bio-Pharmaceutical, recombinant human interleukin-2recombinant TNF receptor 2-Fc fusion protein mutant , RG-6125, RhuDex,rifabutin with clarithromycin with clofazimine, rituximab, rituximabbiosimilar, rituximab follow-on biologic, RPI-78, SAN-300, sarilumab,SBI-087, seliciclib, SHR-0302, sirukumab, spebrutinib, SSS-07,KDDF-201110-06, Syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079,tarenflurbil (transdermal spraygel, skin disease/rheumatoid arthritis),MIKA Pharma/GALENpharma, technetium Tc 99m tilmanocept, technetium[99Tc]methylenediphosphonate, tenoxicam, Debio-0512, tocilizumab, tofacitinib,Trichuris suis ova, umbilical cord-derived mesenchymal stem cells (iv,RA/liver disease), Alliancells/Zhongyuan Union, ustekinumab, VAY-736,VB-201, WF-10, XmAb-5871, YHB-1411-2; 14-3-3 protein eta inhibitors,such as anti-AGX-020 mAbs (rheumatoid arthritis), Augurex;5-Lipoxygenase inhibitors, such as tenoxicam, darbufelone, tebufelone,licofelone, ZD-2138, etalocib, tenidap, tepoxalin, flobufen, SKF-86002,PGV-20229, L-708780, WY-28342, T-0757, T-0799, ZM-216800, L-699333,BU-4601A, SKF-104351, CI-986; Ab1 tyrosine kinase inhibitors, such asimatinib; ACTH receptor agonists, such as FAR-404, metenkefalin acetatewith tridecactide acetate; Adenosine A3 receptor agonists, such asCF-101; Adenosine deaminase inhibitors, such as cladribine, pentostatin,FR-221647; ADP ribosyl cyclase-1 modulators, such as indatuximabravtansine; ADP ribosylation factor 6 inhibitors, such as NAV-2729;Adrenocorticotrophic hormone ligands, such as corticotropin,Mallinckrodt, FAR-404, metenkefalin acetate with tridecactide acetate;Aggrecanase-2 inhibitors, such as GIBH-R-001-2; Albumin modulators, suchas ALX-0061, ONS-1210; AP1 transcription factor inhibitors, such asT-5224, tarenflurbil, SP-10030; Basigin inhibitors, such as ERG-240; Bcrprotein inhibitors, such as imatinib; B-lymphocyte antigen CD19inhibitors, such as XmAb-5871, MDX-1342; B-lymphocyte antigen CD20inhibitors, such as ocrelizumab, ofatumumab, rituximab, rituximabbiosimilar, veltuzumab, rituximab follow-on biologic, ocaratuzumab,BLX-301, IDEC-102, ABP-798, GP-2013, MK-8808, HLX-01, CT-P10, TL-011,PF-05280586, IBPM-001RX, AME-133v, BCD-020, BT-D004, SAIT-101;B-lymphocyte antigen CD20 modulators, such as rituximab biosimilar,SBI-087, TRU-015, DXL-625; B-lymphocyte stimulator ligand inhibitors,such as belimumab, RCT-18, blisibimod, tabalumab, atacicept, briobacept;Bradykinin receptor modulators, such as givinostat; BRAF geneinhibitors, such as binimetinib; Branched amino acid aminotransferase 1inhibitors, such as ERG-240; Bromodomain containing protein inhibitors,such as RVX-297, ZEN-003694; Btk tyrosine kinase inhibitors, such asacalabrutinib, HM-71224, spebrutinib, BTK inhibitor (rheumatoidarthritis), Humanwell Healthcare/Wuxi AppTech, BMS-986142, TAK-020,ONO-4059, TAS-5315, ABBV-105, AC-0025, RN-486, CG-026806, GDC-0834;Cadherin-11 antagonists, such as RG-6125; Calcineurin inhibitors, suchas HS-378, ciclosporin; Calcium channel inhibitors, such as RP-3128;Carbonic anhydrase inhibitors, such as polmacoxib; Cathepsin Kinhibitors, such as CRA-013783, T-5224, AM-3876, VEL-0230, NPI-2019;Cathepsin S inhibitors, such as MIV-247, AM-3876, RWJ-445380, NPI-2019;CCR1 chemokine antagonists, such as BX-471, BMS-817399, BI-638683,CCX-354, MLN-3701, MLN-3897, CP-481715, PS-375179; CCR2 chemokineantagonists, such as MK-0812, AZD-6942; CCR3 gene modulators, such asCM-102; CCRS chemokine antagonists, such as maraviroc, OHR-118,NIBR-6465, AZD-5672, AZD-8566; CD126 antagonists, such as sarilumab;CD29 modulators, such as PF-06687234; CD3 modulators, such asotelixizumab; CD39 agonists, such as AAVS-CD39/CD73 (rheumatoidarthritis), Arthrogen; CD4 agonists, such as maraviroc; CD4 antagonists,such as tregalizumab, zanolimumab, MTRX-1011A, BW-4162W94, EP-1645,clenoliximab; CD40 ligand inhibitors, such as dapirolizumab pegol; CD40ligand receptor antagonists, such as BI-655064, anti-CD40-XTEN,teneliximab; CD40 ligand receptor modulators, such as CFZ-533; CD52antagonists, such as alemtuzumab; CD73 agonists, such as AAVS-CD39/CD73(rheumatoid arthritis), Arthrogen; CD79b modulators, such as MGD-010;CD80 antagonists, such as RhuDex, XENP-9523, ASP-2408, abataceptbiobetter; CD86 antagonists, such as ES-210, abatacept biosuperior,ASP-2408, XENP-9523; CD95 antagonists, such as DE-098, CS-9507; Celladhesion molecule inhibitors, such as natalizumab, alicaforsen,NPC-17923, TK-280, PD-144795; Choline kinase inhibitors, such as cholinekinase inhibitors (rheumatoid arthritis), UC San Diego; Clusterinstimulators, such as alemtuzumab; Complement C5 factor inhibitors, suchas eculizumab, antisense oligonucleotides (rheumatoid arthritis), LeidenUniversity Medical Center; Complement Factor stimulators, such asCM-101; C-reactive protein inhibitors, such as IB-RA (oral, rheumatoidarthritis), Innobioscience, ISIS-353512; CSF-1 antagonists, such asmasitinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578,PD-360324, JNJ-28312141; CXC10 chemokine ligand inhibitors, such as946414-98-8, BMS-936557; CXCR4 chemokine antagonists, such asplerixafor; Cyclin-dependent kinase inhibitor 1 inhibitors, such asCDK-1/2/5/7/9 inhibitors (cancer/tumorogenesis/rheumatoid arthritis),BioPatterns; Cyclin-dependent kinase-2 inhibitors, such as seliciclib,BP-14; Cyclin-dependent kinase-4 inhibitors, such as CDK-4/6 inhibitor(rheumatoid arthritis), Teijin; Cyclin-dependent kinase-5 inhibitors,such as BP-14; Cyclin-dependent kinase-6 inhibitors, such as CDK-4/6inhibitor (rheumatoid arthritis), Teijin; Cyclin-dependent kinase-7inhibitors, such as BP-14, seliciclib; Cyclin-dependent kinase-9inhibitors, such as BP-14, seliciclib; Cyclooxygenase 2 inhibitors, suchas celecoxib, etoricoxib, polmacoxib, laflunimus, etodolac, meloxicam,IB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral,rheumatoid arthritis), Innobioscience, SKLB-023, meloxicam, lumiracoxib;Cyclooxygenase 2 modulators, such as DRGT-46; Cyclooxygenase inhibitors,such as aceclofenac, diclofenac, imidazole salicylate, naproxcinod,naproxen etemesil, misoprostol with diclofenac, nabumetone, naproxenwith esomeprazole, naproxen with esomeprazole strontium , once-dailynaproxen (oral controlled release, pain), Alvogen, pelubiprofen,LY-210073, tenoxicam, licofelone, NS-398, bromfenac, L-746483,LY-255283, tenidap, tepoxalin, flobufen, ibuprofen , flurbiprofen ,SKF-86002, SC-57666, WY-28342, CI-986, bermoprofen; Cytosolicphospholipase A2 inhibitors, such as AVX-002; Cytotoxic T-lymphocyteprotein-4 modulators, such as belatacept, ES-210; Cytotoxic T-lymphocyteprotein-4 stimulators, such as abatacept, abatacept biosimilar,BMS-188667; DHFR inhibitors, such as methotrexate, MPI-2505, MBP-Y003;Diamine acetyltransferase inhibitors, such as diminazene aceturate;Dihydroorotate dehydrogenase inhibitors, such as DHODH inhibitors(rheumatoid arthritis/autoimmune diseases), East China University ofScience and Technology, ASLAN-003, laflunimus, leflunomide, HWA-486,ABR-224050; Elongation factor 2 inhibitors, such as denileukin diftitox;Eotaxin 2 ligand inhibitors, such as CM-102; EP4 prostanoid receptorantagonists, such as CR-6086; Erythropoietin receptor agonists, such ascibinetide; Fas ligands, such as AP-300; FGF-2 ligand inhibitors, suchas RBM-007; FK506 binding protein-12 modulators, such as temsirolimus;Folate antagonists, such as methotrexate, MBP-Y003; Folate receptoragonists, such as folate receptor modulators (chimeric protein,cancer/rheumatoid arthritis), Proda Biotech; Folate receptor modulators,such as technetium (99mTc) etarfolatide; Fractalkine ligand inhibitors,such as E-6011; Fyn tyrosine kinase inhibitors, such as masitinib,laflunimus; G protein coupled receptor 15 antagonists, such as GPR15antagonists (rheumatoid arthritis/HIV-mediated enteropathy), Omeros;GABA A receptor modulators, such as laflunimus; Glucocorticoid agonists,such as prednisolone, fosdagrocorat; Glucocorticoid antagonists, such asREC-200; Glucocorticoid induced leucine zipper stimulators, such asART-G01; GM-CSF ligand inhibitors, such as namilumab, MORAb-022,lenzilumab; GM-CSF receptor antagonists, such as mavrilimumab; GM-CSFreceptor modulators, such as GSK-3196165; Growth regulated protein alphaligand inhibitors, such as T-5224; Hwith Kwith ATPase inhibitors, suchas naproxen with esomeprazole, naproxen with esomeprazole strontium,ketoprofen with omeprazole, KEO-25001, HC-1004, PN-40020; Histamine H4receptor antagonists, such as toreforant, GD-48; Histone deacetylaseinhibitors, such as givinostat, CHR-5154; Histone deacetylase-6inhibitors, such as CKD-506; HIV-1 gp120 protein inhibitors, such asmaraviroc; HLA class II antigen DQ-2 alpha modulators, such as NexVax2;HLA class II antigen inhibitors, such as HLA-DR1/DR4 inhibitors(rheumatoid arthritis), Provid; HLA class II antigen modulators, such asARG-301, recombinant T-cell receptor ligand (rheumatoid arthritis),Artielle; Hsp 70 family inhibitors, such as gusperimus trihydrochloride;Hypoxia inducible factor-1 inhibitors, such as 2-methoxyestradiol; IFNBgene stimulators, such as ART-102; I-kappa B kinase beta inhibitors,such as IMD-2560, IMD-0560; I-kappa B kinase inhibitors, such asbardoxolone methyl; IL-1 antagonists, such as rilonacept, antisenseoligonucleotides (rheumatoid arthritis), Leiden University MedicalCenter, recombinant human interleukin-1 receptor antagonist (rheumatoidarthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceutical; IL-10agonists, such as peg-ilodecakin; IL-11 agonists, such as oprelvekin;IL-12 antagonists, such as ustekinumab, briakinumab, ddRNAi therapy(rheumatoid arthritis), Medistem/Benitec; IL-15 antagonists, such asAMG-714, BNZ-132-2; IL-17 antagonists, such as ixekizumab, secukinumab,KD-025; IL-17 receptor modulators, such as CNTO-6785; IL-2 agonists,such as interleukin-2 follow-on biologic; IL-2 antagonists, such asIB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral,rheumatoid arthritis), Innobioscience, BNZ-132-2; IL-21 antagonists,such as NN-8828, BNZ-132-2; IL-23 antagonists, such as ustekinumab,briakinumab; IL-3 antagonists, such as anti-IL-3 mAbs (rheumatoidarthritis), University of Regensburg; IL-4 agonists, such asSER-130-AMI; IL-6 antagonists, such as olokizumab, clazakizumab,sirukumab, SA-237, tocilizumab, ALX-0061, FB-704A, OP-R003, peptide IL-6antagonist, MEDI-5117, T-5224, humanized anti-IL-6 mAb, tocilizumabbiosimilar, IL-6 neutralizing human antibodies, anti-IL6 antibody,RN-486, BLX-1002, AMG-220, FM-101, K-832, BLX-1025, esonarimod, TA-383;IL-6 receptor modulators, such as tocilizumab, tocilizumab biosimilar,RO-4877533; Immunoglobulin antagonists, such as iguratimod;Immunoglobulin G1 agonists, such as canakinumab, infliximab biobetter,infliximab biosimilar, BX-2922, STI-002, HF-1020; Immunoglobulin G1antagonists, such as YHB-1411-2; Immunoglobulin G1 modulators, such asCFZ-533, lenzilumab; Immunoglobulin G2 antagonists, such as denosumab;Immunoglobulin G2 modulators, such as PF-547659; Immunoglobulin gamma Fcreceptor II modulators, such as MGD-010; Immunoglobulin gamma Fcreceptor IIB antagonists, such as XmAb-5871; Immunoglobulin kappamodulators, such as lenzilumab; Immunoglobulin M antagonists, such asIB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral,rheumatoid arthritis), Innobioscience; Inducible nitric oxide synthaseinhibitors, such as SKLB-023; Inosine monophosphate dehydrogenaseinhibitors, such as mycophenolate mofetil; Insulin sensitizers, such asrosiglitazone, THR-0921, HE-3286, BLX-1002; Integrin alpha-1/beta-1antagonists, such as SAN-300; Integrin alpha-4/beta-1 antagonists, suchas natalizumab; Integrin antagonists, such as PEG-HM-3, CY-9652;Interferon beta ligands, such as recombinant interferon beta-1a, TA-383;Interferon gamma ligands, such as interferon gamma follow-on biologic;Interleukin 17A ligand inhibitors, such as ABT-122, bimekizumab,ABBV-257; Interleukin 17F ligand inhibitors, such as bimekizumab;Interleukin 23A inhibitors, such as guselkumab; Interleukin ligands,such as IBPB-007-IL; Interleukin receptor 17A antagonists, such asbrodalumab; Interleukin-1 beta ligand inhibitors, such as canakinumab,rilonacept, T-5224, gevokizumab, BLX-1002, LY-2189102, PMI-001, K-832,CDP-484; Interleukin-10 ligands, such as PF-06687234; Interleukin-2ligands, such as denileukin diftitox, recombinant interleukin-2,interleukin-2 follow-on biologic, recombinant human interleukin-2,interleukin-2 (injectable); Interleukin-4 ligands, such as Tetravil;Interleukin-6 ligand inhibitors, such as gerilimzumab, PF-4236921; Itktyrosine kinase inhibitors, such as ARN-4079; JAK tyrosine kinaseinhibitors, such as tofacitinib, SHR-0302, cerdulatinib, peficitinib,deuterated tofacitinib analog, SD-900, CVXL-0074; Jak1 tyrosine kinaseinhibitors, such as ABT-494, baricitinib, ruxolitinib, filgotinib,tofacitinib, itacitinib, peficitinib, NIP-585, CS-944X, YJC-50018,GLPG-0555, MRK-12; Jak2 tyrosine kinase inhibitors, such as baricitinib,ruxolitinib, CT-1578; JAK3 gene inhibitors, such as GBL-5b; Jak3tyrosine kinase inhibitors, such as decernotinib, tofacitinib,peficitinib, AC-0025, CS-944X, DNX-04042, MTF-003, ARN-4079, PS-020613;Jun N terminal kinase inhibitors, such as IQ-1S; KCNA voltage-gatedpotassium channel-3 modulators, such as MRAD-P1; Kelch like ECHassociated protein 1 modulators, such as dimethyl fumarate; Kit tyrosinekinase inhibitors, such as imatinib, masitinib; LanC like protein 2modulators, such as BT-11; LITAF gene inhibitors, such as GBL-5b;Lymphocyte function antigen-3 receptor antagonists, such as alefacept;Lyn tyrosine kinase inhibitors, such as masitinib; Macrophage mannosereceptor 1 modulators, such as technetium Tc 99m tilmanocept; MAdCAMinhibitors, such as PF-547659; MAP kinase modulators, such as SKLB-023;MAP3K2 gene inhibitors, such as GBL-5b; MAPKAPK5 inhibitors, such asGLPG-0259; Matrix metalloprotease inhibitors, such as GLPG-0259; MCL1gene inhibitors, such as seliciclib; MEK protein kinase inhibitors, suchas binimetinib, AD-GL0001; MEK-1 protein kinase inhibitors, such asbinimetinib; MEK-2 protein kinase inhibitors, such as binimetinib;Membrane copper amine oxidase inhibitors, such as BTT-1023, PRX-167700,vepalimomab; Metalloprotease-2 inhibitors, such as ERG-240;Metalloprotease-9 inhibitors, such as GS-5745, ERG-240; Midkine ligandinhibitors, such as CAB-102; Mitochondrial 10 kDa heat shock proteinstimulators, such as INV-103; mTOR complex 1 inhibitors, such aseverolimus; mTOR inhibitors, such as everolimus, temsirolimus; NAD ADPribosyltransferase stimulators, such as denileukin diftitox; NAMPT geneinhibitors, such as ART-D01; NF kappa B inhibitor stimulators, such asdenosumab; NFAT gene inhibitors, such as T-5224; NFE2L2 genestimulators, such as bardoxolone methyl; Nicotinic acetylcholinereceptor antagonists, such as RPI-78, RPI-MN; NK cell receptormodulators, such as masitinib; NKG2 A B activating NK receptorantagonists, such as monalizumab; NKG2 D activating NK receptorantagonists, such as NNC-0142-002; Nuclear erythroid 2-related factor 2stimulators, such as dimethyl fumarate; Nuclear factor kappa Binhibitors, such as bardoxolone methyl, IB-RA (injectable, rheumatoidarthritis), Innobioscience, dehydroxymethylepoxyquinomicin, HE-3286,IMD-0560, MP-42, tarenflurbil, VGX-1027, SKLB-023, SP-650003, MG-132,SIM-916, VGX-350, VGX-300, GIT-027, SP-100030, MLN-1145, NVP-IKK-005;Nuclear factor kappa B modulators, such as REM-1086; Nuclear factorkappa B p105 inhibitors, such as REM-1086; Opioid growth factor receptoragonists, such as metenkefalin acetate with tridecactide acetate,FAR-404; Opioid receptor delta antagonists, such as HS-378; Osteoclastdifferentiation factor antagonists, such as denosumab, cyclicpeptidomimetics (rheumatoid arthritis/osteoporosis), University ofMichigan; Osteoclast differentiation factor ligand inhibitors, such asdenosumab; Oxidoreductase inhibitors, such as etodolac, imidazolesalicylate; P2X7 purinoceptor agonists, such as givinostat; p38 MAPkinase alpha inhibitors, such as VX-745, BMS-582949 prodrugs,BMS-751324; p38 MAP kinase inhibitors, such as BCT-197, losmapimod,ARRY-797; PDE 4 inhibitors, such as apremilast; PDE 5 inhibitors, suchas PDES inhibitors (rheumatoid arthritis), University of Rochester; PDGFreceptor agonists, such as oprelvekin; PDGF receptor antagonists, suchas imatinib, masitinib; PDGF-B ligand inhibitors, such as SL-1026; PERKgene inhibitors, such as binimetinib; Phosphoinositide-3 kinase deltainhibitors, such as duvelisib, RP-6503, CT-732, INK-007, GNE-293;Phosphoinositide-3 kinase gamma inhibitors, such as duvelisib, RP-6503;Phospholipase A2 inhibitors, such as AVX-002, human secretedphospholipase A2 type IIA-integrin binding inhibiting peptides(rheumatoid arthritis/asthma/Alzheimer's disease/cancer), University ofCalifornia, Davis, AK-106, varespladib methyl, Ro-31-4493, BM-162353,Ro-23-9358, YM-26734; Platelet activating factor receptor antagonists,such as piperidone hydrochloridum; PPAR gamma agonists, such asrosiglitazone, THR-0921, rosiglitazone XR, etalocib; Programmed celldeath protein 1 modulators, such as INSIX RA; Prostaglandin D synthasestimulators, such as HF-0220; Protein arginine deiminase inhibitors,such as PAD inhibitors (rheumatoid arthritis), Leiden University MedicalCenter/LURIS; Protein tyrosine kinase inhibitors, such as leflunomide;PurH purine biosynthesis protein inhibitors, such as mycophenolatemofetil; Rho associated protein kinase 2 inhibitors, such as KD-025;Seprase inhibitors, such as anti-fibroblast-activation protein (FAP)antibody radiotracers (rheumatoid arthritis), Hoffmann-La Roche/RadboudUniversity; Signal transducer CD24 modulators, such as CD24-IgFc; Signaltransduction inhibitors, such as imatinib; Sodium glucose transporter-2inhibitors, such as THR-0921; Sphingosine 1 phosphate phosphatasemodulators, such as S1P modulators (oral, multiple sclerosis/ulcerativecolitis/rheumatoid arthritis), Akaal Pharma; STAT3 gene inhibitors, suchas bardoxolone methyl, vidofludimus; Superoxide dismutase stimulators,such as imisopasem manganese; SYK family tyrosine kinase inhibitors,such as MK-8457; Syk tyrosine kinase inhibitors, such as fostamatinib,entospletinib, KDDF-201110-06, HMPL-523, cerdulatinib, AB-8779, GS-9876,PRT-2607, CVXL-0074, CG-103065and CG-026806; Syndecan-1 inhibitors, suchas indatuximab ravtansine; T cell receptor antagonists, such as TCRinhibiting SCHOOL peptides (systemic/topical, rheumatoidarthritis/dermatitis/scleroderma), SignaBlok, CII modified peptide(rheumatoid arthritis), Peking University; T cell receptor modulators,such as ARG-301; T cell surface glycoprotein CD28 inhibitors, such asabatacept, belatacept, abatacept biosimilar, RhuDex, BMS-188667; T cellsurface glycoprotein CD28 stimulators, such as TAB-08; TAK1 bindingprotein modulators, such as epigallocatechin 3-gallate; Talinmodulators, such as short-form talin regulators (rheumatoid arthritis),KayteeBio; T-cell differentiation antigen CD6 inhibitors, such asitolizumab; T-cell surface glycoprotein CD8 inhibitors, such astregalizumab; Tenascin modulators, such as Tetravil; TGF beta agonists,such as tregalizumab; Thymulin agonists, such as Syn-1002; TLR-2antagonists, such as VB-201, P-13; TLR-4 antagonists, such as VB-201,P-13; TLR-9 antagonists, such as P-13; TNF alpha ligand inhibitors, suchas adalimumab biosimilarYHB-1411-2, adalimumab, infliximab, infliximabbiosimilar, recombinant humanized anti-TNF-alpha monoclonal antibody,certolizumab pegol, golimumab, ozoralizumab, AT-132, etanerceptbiosimilar, ISIS-104838, ISU-202, CT-P17, MB-612, Debio-0512, anti-TNFalpha human monoclonal antibody, infliximab biobetter, UB-721, KN-002,DA-3113, BX-2922, R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420,GS-071, ABP-710, STI-002, BOW-015, FKB-327, BAX-2200, HLX-03, BI-695501,CNTO-148, MYL-1401AABP-501, HOT-3010, BAX-2923, SCH-215596, ABT-D2E7,BAT-1406, XPro-1595, Atsttrin, SSS-07, golimumab biosimilar, TA-101,adalimumab follow-on biologic, BLX-1002, ABX-0401, TAQ-588, golimumabbiosimilar, TeHL-1, placulumab, PMI-001, tgAAV-TNFR:Fc, K-832,CYT-007-TNFQb, SSR-150106, PassTNF, Verigen, DOM-0200, DOM-0215,AME-527, anti-TNF-alpha mAb, GENZ-38167, BLX-1028, CYT-020-TNFQb,CC-1080, CC-1069; TNF alpha ligand modulators, such as MM-A01-01,CDP-571, camobucol; TNF antagonists, such as etanercept, certolizumabpegol, etanercept follow-on biologic, etanercept biosimilar, DNX-114,TNF antagonist with IL-12 antagonist (rheumatoid arthritis), Universityof Oxford, BN-006, SCB-131, pegsunercept, GBL-5b, ACE-772, onercept,DE-096, PN-0615, lenercept, ITF-1779, MDL-201112, BAX-2200, SCB-808,DA-3853, HD-203; TNF gene inhibitors, such as GIBH-R-001-2; TNF receptormodulators, such as recombinant TNF receptor 2-Fc fusion protein mutant,T-0001, tgAAV-TNFR:Fc; TNFSF11 gene inhibitors, such as denosumab;Transcription factor p65 inhibitors, such as REM-1086; Transcriptionfactor RelB inhibitors, such as REM-1086; Transferrin modulators, suchas methotrexate, MBP-Y003; Tumor necrosis factor 13C receptorantagonists, such as VAY-736; Tumor necrosis factor 15 ligandinhibitors, such as anti-TL1A antibodies (rheumatoidarthritis/inflammatory bowel disease), NIAMS; Tumor necrosis factorligand 13 inhibitors, such as atacicept; Tumor necrosis factor ligandinhibitors, such as ABBV-257, etanercept biosimilar, ABT-122; Type IIL-1 receptor antagonists, such as anakinra, anakinra biosimilar,anakinra follow-on biologic, AXXO; Type I TNF receptor antagonists, suchas NM-9405; Type II TNF receptor modulators, such as etanercept,SCB-131, etanercept biosimilar, etanercept follow-on biologic, BAX-2200,SCB-808, LBEC-0101, DMB-3853, DWP-422, BT-D001, DA-3853; UnspecifiedGPCR agonists, such as NCP-70X; VEGF receptor antagonists, such as2-methoxyestradiol and NSC-650853, SL-1026; VEGF-2 receptor antagonists,such as CG-026806; VEGF-2 receptor modulators, such as VEGFR2neutralizing antibody (rheumatoid arthritis), University of Rochester;VEGF-B ligand inhibitors, such as CSL-346; X-linked inhibitor ofapoptosis protein inhibitors, such as IAP inhibitors (oral),Pharmascience; and Zap70 tyrosine kinase inhibitors, such as MK-8457,CT-5332.

Combinations for Metabolic Diseases or Conditions

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides. Examples of therapeutic agents used to treatmetabolic disorders include antihypertensive agents and lipid loweringagents. Additional therapeutic agents used to treat metabolic disordersinclude insulin, sulfonylureas peroxisome proliferator activatedreceptor gamma (PPAR-γ) agonists, such as thiazolidinediones such aspioglitazones, biguanides, alpha-glucosidase inhibitors, Vitamin E andincretin mimetics. Thus, one aspect of the disclosure is a method oftreating a metabolic disease comprising administering a compound of thedisclosure in combination with one or more compounds useful for thetreatment of metabolic diseases to a subject, particularly a humansubject, in need thereof.

Pharmaceutical Compositions

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations(compositions). The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, as abovedefined, together with one or more acceptable carriers therefor andoptionally other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and physiologically innocuous to the recipientthereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withinactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.)which constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

In certain embodiments, formulations suitable for oral administrationare presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.

In certain embodiments, the pharmaceutical formulations include one ormore compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that is combined with the inactiveingredients to produce a dosage form will vary depending upon the hosttreated and the particular mode of administration. For example, in someembodiments, a dosage form for oral administration to humans containsapproximately 1 to 1000 mg of active material formulated with anappropriate and convenient amount of carrier material (e.g., inactiveingredient or excipient material). In certain embodiments, the carriermaterial varies from about 5 to about 95% of the total compositions(weight: weight). In some embodiments, the pharmaceutical compositionsdescribed herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1to 200 mg, 1 to 100 mg or 1 to 50 mg of the compound of Formula I, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions described herein contain not more than about400 mg of the compound of Formula I. In some embodiments, thepharmaceutical compositions described herein contain about 100 mg of thecompound of Formula I, or a pharmaceutically acceptable salt thereof.

It should be understood that in addition to the ingredients particularlymentioned above the formulations disclosed herein may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Veterinary compositions comprising at least one active ingredient asabove defined together with a veterinary carrier are further provided.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds of Formula I (herein referred to as the activeingredients), or a pharmaceutically acceptable salt thereof, areadministered by any route appropriate to the condition to be treated.Suitable routes include oral, rectal, nasal, topical (including buccaland sublingual), vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. It will be appreciated that the preferred route may vary withfor example the condition of the recipient. An advantage of thecompounds of this invention is that they are orally bioavailable and canbe dosed orally. Accordingly, in one embodiment, the pharmaceuticalcompositions described herein are oral dosage forms. In certainembodiments, the pharmaceutical compositions described herein are oralsolid dosage forms.

Formulation Example 1

-   Hard gelatin capsules containing the following ingredients are    prepared:

Ingredient Quantity (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0 The above ingredients are mixed and filled intohard gelatin capsules.

Formulation Example 2

-   A tablet Formula is prepared using the ingredients below:

Ingredient Quantity (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0The components are blended and compressed to form tablets.

Formulation Example 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Formulation Example 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Ingredient Quantity (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Formulation Example 5

-   Suppositories, each containing 25 mg of active ingredient are made    as follows:

Ingredient Amount Active Ingredient 25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 6

-   Suspensions, each containing 50 mg of active ingredient per 5.0 mL    dose are made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Formulation Example 7

-   A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

Formulation Example 8

-   An injectable preparation is prepared having the following    composition:

Ingredients Amount Active ingredient 2.0 mg/mL Mannitol, USP 50 mg/mLGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0mL Nitrogen Gas, NF q.s.

Formulation Example 9

-   A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients and water thenadded q.s. 100 g.

Formulation Example 10 Sustained Release Composition

Ingredient Weight Range % Active ingredient 50-95 Microcrystallinecellulose (filler)  1-35 Methacrylic acid copolymer  1-35 Sodiumhydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0 Magnesiumstearate 0.5-5.0

Sustained release formulations of this disclosure may be prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed(dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate) andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma) and the like. These film-forming agents may optionally containcolorants, plasticizers and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e., the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

Formulation Example 11

-   A tablet Formula Is prepared using the ingredients below:

Ingredient Quantity (mg/tablet) Active Ingredient 300.0 Cellulose,microcrystalline 100.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0The components are blended and compressed to form tablets.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

List of Abbreviations and Acronyms

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl aq. Aqueous ATPAdenosine triphosphate B₂Pin₂ Bis(pinacolato)diboron BOCtert-Butoxycarbonyl Br Broad BSA Bovine serum albumin D Doublet DCMDichloromethane Dd Doublet of doublets Ddd Doublet of doublet ofdoublets DIPEA N,N-Diisopropylethylamine (Hünig's Base) DMADimethylacetamide DME 1,2-Dimethoxyethane DMF Dimethylformamide DMSODimethylsulfoxide Dt Doublet-triplet DTT Dithiothreitol (Cleland'sreagent) EC₅₀ The half maximal effective concentration EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDTAEthylenediaminetetraacetic acid EGFR Epidermal growth factor receptor EqEquivalents ES/MS Electrospray mass spectrometry Et Ethyl EtOAc Ethylacetate Et0H Ethanol (Ethyl alc0Hol) FBS Fetal bovine serum G Grams HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HCl Hydrochloric acid HPLC High pressure liquidchromatography Hrs Hours HERE ® Homogeneous time resolved fluorescence,a registered trademark of Cisbio Bioassays, parc marcel boiteux 30200codolet, France Hz Hertz IBD Inflammatory bowel disease IC₅₀Half-maximal inhibitory concentration i-pr Isopropyl J Coupling constant(MHz) K₃PO₄ Tripotasium phosphate KOtBu Potassium tert-butoxide KOAcPotassium Acetate Lawesson's 2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-Reagent diphosphetane 2,4-disulfide LCMS Liquid chromatography-massspectrometry Li HMDS Lithium bis(trimethylsilyl)amide Li0H Lithiumhydroxide LiI Lithium iodide LPS Lipopolysaccharide M Molar M MultipletM+ Mass peak M + H+ Mass peak plus hydrogen Me Methyl MeCN AcetonitrileMe0H Methanol (Methyl alc0Hol) MeLi Methyllithium MeMgX Methylmagnesiumhalide (Grignard reagent), where X is Fluoro, Chloro, Bromo or IodoMe₆Sn₂ Hexamethyldistannane (hexamethylditin) Mg Milligram MgSO₄Magnesium sulfate MHz Megahertz Min Minute ml/mL Milliliter mMMillimolar Mmol Millimole MS Mass spectroscopy MsCl Mesyl chloride NBSN-Bromosuccinimide n- Normal nBu/Bu n-Butyl (normal Butyl) n-BuLin-Butyl Lithium NaH Sodium hydride NaHCO₃ Sodium bicarbonate NaN₃ Sodiumazide Na₃PO₄ Trisodium phosphate Na₂SO₄ Sodium sulfate nL Nanoliter NmNanometer NMP 1-methylpyrrolidin-2-one NMR Nuclear magnetic resonanceNP-40 Nonyl phenoxypolyethoxylethanol Pd-PEPPSI ™-[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2- IPentylidene](3-chloropyridyl)palladium(II) dichloride Pen-StrepPenicillin-Streptomycin (5,000 units of penicillin G sodium salt, and5,000 μg streptomycin sulfate in 0.85% saline) Ph Phenyl Q Quartet q.s.Quantity sufficient to achieve a stated function RP Reverse phase RPMIRoswell Park Memorial Institute medium Rt Room temperature S Singletsat. Saturated Selectfluor ® 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis (a trademark of Air Products andChemicals) SFC Supercritical fluid chromatography SiliaMetS ®Silica-based Palladium scavenger, registered Thiol trademark ofSilicycle T Triplet THF Tetrahydrofuran TFA Trifluoroacetic acid XPhosPd G3 (2-Dicycl0Hexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II)methanesulfonate

Experimental Procedures General Schemes

The compounds of formula 1.5 may be accessed according to the methodoutlined in Scheme 1. 1-aminopyrrole 1.1 may be condensed with asuitable coupling partner to produce substitutedpyrrolo[1,2-b]pyridazine 1.2 using a suitable catalyst (e.g., HCl, etc.)and suitable solvent (e.g., EtOH, etc.). Halogenation at the positionshown using a known halogenating reagent (e.g., NBS, etc.) can form theintermediate 1.3, which can be further substituted either via C—Hactivation or electrophilic aromatic substitution with a suitablereagent (e.g., selectfluor, etc.) to produce intermediate 1.4. Halogenmetal exchange of —X to -M can then be achieved using a suitable reagent(e.g., n-BuLi, etc.) or transition metal coupling using a palladiumcatalyst and metal source (e.g., B₂Pin₂, Me₆Sn₂, etc.) to giveintermediate 1.5.

The compounds of the formula 2.3 may be accessed according to the methodoutlined in Scheme 2. The acid 2.1 can be converted to the correspondingacyl hydrazine using a coupling reagent (e.g., HATU, etc.) in thepresence of a base (e.g., DIPEA, etc.). Cyclization of compound 2.2 canbe accomplished by heating in the presence of a thionating reagent(e.g., Lawesson's reagent, etc.) to provide compound 2.3.

The compounds of formula 3.6 may be accessed according to the methodoutlined in Scheme 3. Dihalopyridine 3.1 may be converted to compound3.2 via displacement of one of the halogen groups (e.g., nucleophilicaromatic substitution, etc.). Further functionalization of compound 3.2using a metal-containing heterocyclic species (e.g., compound 1.5) witha suitable catalyst, such as a palladium catalyst, can afford compound3.3. Halogenation at the position shown using a known halogenatingreagent (e.g., NB S, etc.) can form the intermediate 3.4 which can befurther substituted through a cross-coupling reaction using a suitablecatalyst, such as a palladium catalyst, to provide compound 3.5.

Compounds of formula 4.2 may be assembled following Scheme 4.Displacement of the halogen group (e.g., nucleophilic aromaticsubstitution, etc.) of a halothiadiazole 4.1 with a nucleophile (e.g.,an amine, etc.) can provide compound 2.3. Halogenation at the positionshown using a known halogenating reagent (e.g., NB S, etc.) can form theintermediate 4.2.

Compounds of formula 3.5 may also be assembled following Scheme 5.Halogen metal exchange of —X to -M can then be achieved using a suitablereagent (e.g., n-BuLi, etc.) or transition metal coupling using apalladium catalyst and metal source (e.g., B₂Pin₂, Me₆Sn₂, etc.) to giveintermediate 5.1. Functionalization of compound 5.1 can be doneutilizing a cross-coupling reaction with compound 4.2 using a suitablecatalyst, such as a palladium catalyst, to provide compound 3.5.

An alternative method of access compound 3.5 is shown in Scheme 6.Starting from the nicotinic acid 6.1 , the corresponding acyl hydrazinecan be prepared using a coupling reagent (e.g., HATU, etc.) in thepresence of a base (e.g., DIPEA, etc.). Cyclization of compound 6.3 canbe accomplished by heating in the presence of a thionating reagent(e.g., Lawesson's reagent, etc.) to provide compound 6.4. Furtherfunctionalization of compound 6.4 using a metal-containing heterocyclicspecies (e.g., compound 1.5) with a suitable catalyst, such as apalladium catalyst, can afford compound 3.5.

It is also noted that synthetic manipulations of the incorporated Rgroups are possible following their incorporation. A specificillustrative example of an alteration to the R² group is shown in Scheme7 wherein the secondary carbamate 7.1 is converted the primary amine7.2. Other functional groups may also be present in the R² and can bemanipulated. These groups and manipulations can include, but are notlimited to, oxidation, elimination or displacement using suitablereagents known to those skilled in the art. The order of syntheticmanipulations may be carried out in a fashion that is consistent withthe methods outlined in Schemes 1-6 and should not be limited to thefinal step of compound preparation.

Synthesis of Intermediates Preparation of Intermediate I-1:

tert-butyl ((1r,40-4-(2-formylhydrazine-1-carbonyl)cyclohexyl)carbamate:To a solution of(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (250mg, 1.0 mmol) in DMF (2 mL) was added formic acid hydrazide (80 mg, 1.3mmol), HATU (469 mg, 1.2 mmol), and finally DIPEA (0.45 mL, 2.6 mmol)and the resulting mixture stirred at room temperature for 15 minutes.Upon completion, the reaction mixture was poured into water (5 mL) andextracted with EtOAc (2×15 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated. The resulting crude residue waspurified by silica gel chromatography (eluent: EtOAc/hexanes) to givethe desired product.

ES/MS: 285.9 [M+H]³⁰

tert-butyl ((1r,4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate: To asolution of tert-butyl((1r,4r)-4-(2-formylhydrazine-1-carbonyl)cyclohexyl)carbamate (193 mg,0.68 mmol) in dioxane (5 mL) was added Lawesson's Reagent (301 mg, 0.74mmol) and the resulting reaction mixture heated to 100° C. for 3 hours.Upon completion, the reaction mixture was poured into water (5 mL) andextracted with EtOAc (2×15 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated. The resulting crude residue waspurified by silica gel chromatography (eluent: EtOAc/hexanes) to givethe desired product.

ES/MS: 284.0 [M+H]⁺

(1r,4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexan-1-amine hydrochloride:tert-butyl ((1r,4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate (59mg, 0.21 mmol) was then dissolved in HCl (4.0M in dioxane, 4 mL, 16mmol) and stirred at room temperature for 7 hours after which thereaction mixture was concentrated to dryness directly to give thedesired product as an HCl salt which was used without furtherpurification.

ES/MS: 184.1 [M+H]⁺

N-((1r, 4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide (I-1):(1r,4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexan-1-amine hydrochloride (175mg, 0.8 mmol) was dissolved in CH₂Cl₂ (4 mL) and the reaction mixturewas cooled to 0° C. Triethylamine (0.33 mL, 2.39 mmol) was added,followed by acetic anhydride (0.094 mL, 1 mmol). The reaction wasstirred at 0° C. for 30 minutes after which the mixture was diluted withCH₂Cl₂ and washed with water. The organic layer was dried over MgSO₄,filtered, and concentrated. The crude material was purified by silicagel chromatography (eluent EtOAc/hexanes followed by methanol/EtOAc) togive I-1.

ES/MS: 226.1 [M+H]⁺

The following intermediates were synthesized as described for I-1 usingthe appropriate starting carboxylic acid, and appropriate anhydride,carbonyl-chloride, or alkyl triflate:

Preparation of Intermediate I-2:

2-bromo-N-isopropylpyridin-4-amine: To a solution of2-bromo-4-fluoropyridine (1.0 g, 5.68 mmol) in NMP (10 mL) was addedisopropylamine (0.8 mL, 12.02 mmol) and N,N-diisopropylethylamine (1.25mL, 7.18 mmol). The resulting mixture was heated for 30 minutes at 150°C. in a microwave after which the reaction contents were diluted withEtOAc and washed three times with water. The organic layer was driedover MgSO₄, filtered and concentrated. The resulting material waspurified normal phase SiO₂ chromatography (eluent: ethylacetate/hexanes) to provide the desired product.

ES/MS: 215.2 (M+H⁺)

7-(4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile:To a solution of 2-bromo-N-isopropylpyridin-4-amine (1.18 g, 5.14 mmol),(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)boronic acid (2.1 g, 10.34 mmol)(the corresponding pinacol boronic ester is equally competent in thistransformation) and Xphos Pd G3 (0.31 g, 0.37 mmol) in DME (12.3 mL) wasadded aqueous potasium phosphate (2M, 4.9 mL, 9.9 mmol). The resultingsolution was degassed with argon for 2 min and heated under microwaveconditions for 40 min at 120° C. after which silica gel was added, andthe resulting slurry was filtered through celite, rinsing with EtOAc.The material was concentrated, and the resulting crude material waspurified by normal phase SiO₂ chromatography (eluent: ethylacetate/hexanes) to provide the desired product.

ES/MS: 278.2 (M+H⁺)

7-(5-bromo-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(1-2): To a solution of7-[4-(isopropylamino)-2-pyridyl]pyrrolo[1,2-b]pyridazine-3-carbonitrile(0.75 g, 2.4 mmol) in DCM:MeCN (1:1, 60 mL) at 0° C. was added asolution of N-bromosuccinimide (0.433 g, 2.4 mmol) in 9 mL of 1:1DCM:MeCN, and the resulting mixture stirred at zero degrees. After 30minutes, significant precipitate was observed, and the reaction mixturewas concentrated under vacuum. The crude material was purified by silicagel chromatography (EtOAc/hexanes) to give I-2.

ES/MS: 356.2 (M+H⁺)

The following intermediates were prepared as described forI-2, using theappropriate amine for step 1 or boronate ester/boronic acid for step 2:

Preparation of Intermediate I-3:

(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)boronicacid (I-3): To a microwave vial containing7-(5-bromo-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-2) (120 mg, 0.34 mmol), bis(pinacolato)diboron (171 mg, 0.674 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05mmol), and potassium acetate (99 mg, 1 mmol) was added 1,4-dioxane (1mL) and DMF (0.5 mL). The mixture was degassed with argon for 1 min,sealed, and heated under microwave conditions for 20 min at 120° C.,after which the resulting crude material was filtered and purified byRP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product (I-3) as atrifluoroacetate salt.

ES/MS: 322.2 (M+H⁺)

The following intermediates were prepared as described for I-3 from theappropriate 3-bromo-pyridines:

Preparation of Intermediate I-4:

N-(1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl)acetamide: To a solution of2-bromo-1,3,4-thiadiazole (100.0 mg, 0.61 mmol) andN-(piperidin-4-yl)acetamide hydrochloride (270.7 mg, 1.5 mmol) inn-butanol (1.2 mL) was added N,N-diisopropylethylamine (0.42 mL, 2.4mmol). The reaction mixture was heated thermally at 120° C. for 1 hour.The reaction mixture was cooled, concentrated in vacuo to provide thecrude product that was used without purification.

ES/MS: 227.12 [M+H]⁺.

N-(1-(5-bromo-1,3,4-thiadiazol-2-yl)piperidin-4-yl)acetamide (I-4): To asolution of crude N-(1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl)acetamide(50.0 mg, 0.22 mmol) in DCM (0.5 mL) and MeCN (0.5 mL) was addedN-bromosuccinimide (118.0 mg, 0.66 mmol) in one portion. After stirringat room temperature for 5 minutes, the reaction mixture was concentratedin vacuo and purified by silica gel column chromatography (eluent:MeOH/DCM) to provide I-4.

ES/MS: 305.1, 307.0 [M+H⁺]. Preparation of Intermediate I-5:

7-(5-bromo-1,3,4-thiadiazol-2-yl)-2-oxa-7-azaspiro[3.5]nonane (I-5):7-(5-bromo-1,3,4-thiadiazol-2-yl)-2-oxa-7-azaspiro[3.5]nonane wasprepared as described in Preparation of Intermediate 1-4 substitutingN-(piperidin-4-yl)acetamide hydrochloride with2-oxa-7-azaspiro[3.5]nonane.

ES/MS: 290.3, 292.0 [M+H⁺]. Preparation of Intermediate I-6:

(R)-4-(5-bromo-1,3,4-thiadiazol-2-yl)amino)-3-fluoro-2-methylbutan-2-ol(I-6):(R)-4((5-bromo-1,3,4-thiadiazol-2-yl)amino)-3-fluoro-2-methylbutan-2-olwas prepared as described in Preparation of Intermediate I-4substituting N-(piperidin-4-yl)acetamide hydrochloride with(R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride.

ES/MS: 284.0, 285.9 [M+H⁺]. Preparation of Intermediate I-7:

tert-butyl (2-(1,3,4-thiadiazol-2-yl)ethyl)carbamate (I-7): To asolution of 2-(1,3,4-thiadiazol-2-yl)ethan-1-amine (100.0 mg, 0.77 mmol)and di-tert-butyl dicarbonate (186 mg, 0.85 mmol) in THF at 0° C. wasadded triethylamine (0.13 mL, 0.93 mmol). The reaction mixture waswarmed to room temperature and stirred for 90 minutes. The reactionmixture was concentrated in vacuo and purified by silica gel columnchromatography (eluent: MeOH/DCM) to provide 1-7.

ES/MS: 229.9 [M+H⁺]. Preparation of Intermediate I-8:

3,3-Diethoxy-2-formylpropionitrile Potassium Salt (I-8C): o a stirredsolution of 3,3-diethoxypropane-nitrile (I-8A, 283.80 g, 1.98 moles) andmethyl formate (I-8B, 148.80 g, 2.48 moles) in anhydrous THE (1.1 L) at10° C. was added 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2moles). The temperature was maintained in the range of 10° C. to 15° C.throughout the 45 minute addition. Following the addition, the resultingslurry was stirred for 2 hours at ambient temperature, Hexane (400 mL)was then added and stifling was continued for another 20 min. The slurrywas filtered and the cake washed with 1/1 hexanes/THF and driedovernight at 60° C. in a vacuum oven to provide I-8C. ¹H-NMR (CD₃OD) wasconsistent with the desired structure.

Pyrrolo[1,2-b]pyridazine-3-carbonitrile (I-8E): A stirred suspension of3,3-diethoxy-2-formylpropionitrile potassium salt (I-8C, 5.10 g, 24.36mmol) was cooled to 0° C., and concentrated HCl (7.11 mL, 85.26 mmol)was added dropwise at such a rate that the internal temperature of thereaction did not go above 20° C. After addition was complete, thereaction was stirred at room temperature for 20 minutes. To thisreaction mixture was added a solution of 1-aminopyrrole (I-8D, 1.00 g,12.18 mmol) in methanol (4.0 mL). After addition, the reaction mixturewas refluxed at 90° C. for 2 hours. When heating was complete, thereaction was cooled to room temperature and concentrated to about halfof the original volume. Saturated aqueous sodium bicarbonate was addedcarefully to the resulting residue until bubbling stopped. The solutionwas extracted with two portions of ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered, concentrated in vacuo,and the resulting residue was purified by silica gel chromatography(eluent: EtOAc/hexanes) to provide I-8E.

1H NMR (400 MHz, Chloroform-d) δ 8.16-8.03 (m, 2H), 7.93 (ddd, J=2.6,1.4, 0.6 Hz, 1H), 7.04 (dd, J=4.5, 2.7 Hz, 1H), 6.84 (dd, J=4.6, 1.4 Hz,1H).

7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-8F): To a solution ofpyrrolo[1,2-b]pyridazine-3-carbonitrile (I-8E, 840.0 mg, 5.9 mmol) inMeCN (30 mL) at room temperature was added N-bromosuccinimide in oneportion. The reaction was stirred at room temperature for 30 minutesthen poured into saturated aqueous sodium bicarbonate. The solution wasconcentrated in vacuo to remove the acetonitrile. The resulting aqueouslayer was extracted with three portions of EtOAc. The combined organiclayers were dried over sodium sulfate, filtered, concentrated in vacuo,and purified by silica gel chromatography (eluent: EtOAc/hexanes) toprovide I-8F.

1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.12 (d, J=4.8 Hz, 1H), 6.93 (d, J=4.8 Hz, 1H).

7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-8): A microwave vial was charged with7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-8F, 416.5 mg, 1.9mmol), bis(pinacolato)diboron (762.1 mg, 3.0 mmol), potassium acetate(552.3 mg, 5.6 mmol), and bis(triphenylphosphine)palladium(II)dichloride (65.8 mg, 0.094 mmol). Dioxane (8.0 mL) and DMF (4.0 mL) wereadded, and the reaction mixture was degassed with bubbling argon for 2minutes. The vial was sealed and the reaction was heated at 120° C. in amicrowave reactor for 60 minutes. After cooling, the reaction mixturewas filtered and concentrated in vacuo. The resulting residue waspartitioned between EtOAc and water. The aqueous layer was extractedwith a second portion of EtOAc, and the combined organic layers weredried over sodium sulfate, filtered through a plug of Celite, andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (eluent: EtOAc/hexanes) to provide I-8.

1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.3 Hz, 1H), 8.14 (d, J=2.2Hz, 1H), 7.52 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H), 1.41 (s, 12H).

Preparation of Intermediate I-9:

tert-butyl ((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate: To asolution of(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid(10.0 g, 41.1 mmol) in THF (360 mL) was added 1,1′-carbonyldiimidazole(10.7 g, 65.8 mmol) as a single portion and the resulting mixturestirred for 16 h at room temperature. Hydrazine hydrate (10.0 mL, 206mmol) was then added as a single portion. After 15 minutes approximately200 mL THF was removed by rotary evaporation and the resulting slurryfiltered rinsing with THF. The solid was dried under vacuum to givetert-butyl ((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate which wasused without further purification.

ES/MS: 202.2 (M+H⁺).

tert-butyl((1,4r)-4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamate:To a solution of tert-butyl((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate (1.50 g, 5.83 mmol)and diisopropylethylamine (2.6 mL, 14.9 mmol) in THF (20 mL) was addeddifluoroacetic anhydride (0.93 mL, 7.43 mmol) and the reaction mixtureallowed to stir at room temperature. After 30 minutes additionaldifluoroacetic anhydride (0.40 mL, 3.20 mmol) was added and the reactionmixture allowed to stir for 30 minutes. The reaction mixture was thenpoured into water (20 mL), extracted with EtOAc (2×40 mL), washed withbrine (1×15 mL), dried over MgSO₄, filtered and concentrated to givecrude tert-butyl((1r,4r)-4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamatewhich was used without further purification.

ES/MS: 280.0 (M+H⁺).

tert-butyl((1,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate:To a solution of tert-butyl((1r,4r)-4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamate(1.66 g, 4.96 mmol) in dry acetonitrile (40 mL) was added sequentiallytriphenylphosphine (3.90 g, 14.9 mmol), hexachloroethane (1.76 g, 7.34mmol) and diisopropylethylamine (5.2 mL, 29.7 mmol) and the resultingsolution allowed to stir for 15 minutes at room temperature. Uponcompletion the reaction mixture was poured into saturated aqueous NH₄Cl(30 mL, and extracted with EtOAc (2×60 mL). The combined organics werewashed with brine (1×15 mL), dried over MgSO₄, filtered and concentratedto give a crude residue which was further purified using silica gelchromatography (eluent: EtOAc/hexanes) to give the product tert-butyl((1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate.

(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride (I-9): Tert-butyl((1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate(1.26 g, 3.96 mmol) was dissolved in HCl solution (4.0M in dioxane, 12mL, 48 mmol) and the resulting mixture was stirred in a preheated 50° C.heating block for 30 minutes. Upon completion the suspension wasfiltered directly washing with dioxane (1×4 mL) and the solid driedunder vacuum to give(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride (I-9) which was used without further purification.

ES/MS: 218.0 (M+H⁺). Preparation of Intermediate I-10:

(R)-7-(5-bromo-4-((1-cyanoethyl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-10): A solution of(R)-2-((5-bromo-2-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-4-yl)amino)propanamide(prepared as described for I-2 using the appropriate amine in step 1)(500 mg, 1.30 mmol) in THF (6.5 mL) was cooled to 0° C. To the cooledsolution was added pyridine (0.52 mL, 6.49 mmol) followed bytrifluoroacetic anhydride (0.27 mL, 1.95 mmol). The reaction mixture wasallowed to warm to RT. After 2 hours, trifluoroacetic lanhydride (36 μL,0.26 mmol) was added. The reaction mixture was stirred at RT for anadditional 30 minutes, then concentrated in vacuo and purified by silicagel column chromatography (eluent: MeOH/DCM) to provide I-10.

ES/MS: 367.43, 369.09 [M+H⁺].

Preparation of Intermediate I-11:

(S)-8-(5-bromo-1,3,4-thiadiazol-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (I-11): To a solution of2,5-dibromo-1,3,4-thiadiazole (100 mg, 0.41 mmol) and(S)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (106 mg, 0.49mmol) in 1,4-dioxane (1.0 mL) was added N,N-diisopropylethylamine (0.29mL, 1.64 mmol). The reaction mixture was heated in a sealed vial for onehour, then concentrated in vacuo and purified by silica gel columnchromatography (eluent: MeOH/DCM) to provide I-11.

ES/MS: 305.31, 307.03 [M+H⁺].

The following intermediates were synthesized as described for I-11 usingthe appropriate starting amine:

Preparation of Intermediate I-12:

(1R,5S,8r)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclop.2.11octan-8-aminehydrochloride: To a solution of tert-butyl((1R,5S,8r)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(synthesized as described for I-11) (40.0 mg, 0.10 mmol) in 1,4-dioxane(0.5 mL) was added hydrochloric acid (4M in dioxane, 0.13 mL, 0.51mmol). The reaction mixture was stirred at 40° C. for 90 minutes, thenconcentrated in vacuo and used without additional purification.

ES/MS: 289.17, 291.07 [M+H⁺].

N-((1R,5S,8r)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide(I-12): To a suspension of(1R,5S,8r)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-aminehydrochloride (29.7 mg, 0.10 mmol) in DCM (1.0 mL) was addedtriethylamine (57 μL, 0.41 mmol) followed by acetic anhydride (11.7 μL,0.12 mmol). The reaction mixture was stirred at RT for 10 minutes, thenconcentrated in vacuo and purified by silica gel column chromatography(eluent: MeOH/DCM) to provide I-12.

ES/MS: 331.37, 333.03 [M+H⁺].

The following intermediates were synthesized as described for 1-12 usingthe appropriate amine in step 1, and the appropriate anhydride, acidchloride, chloroformate, or sulfonyl chloride in step 2:

Preparation of Intermediate I-13:

1((1,3,4-thiadiazol-2-yl)amino)-2-methylpropan-2-ol (I-13): To asolution of 2-bromo-1,3,4-thiadiazole (100 mg, 0.61 mmol) and1-amino-2-methyl-propan-2-ol (56 μL, 0.91 mmol) in 1-butanol (1.2 mL)was added N,N-diisopropylethylamine (264 μL, 1.52 mmol). The reactionmixture was stirred in a sealed vial at 120° C. for 1 hour, thenconcentrated and purified by silica gel column chromatography (eluent:MeOH/DCM) to provide I-13.

Preparation of Intermediate I-14:

tert-butyl((1S,2R)-2-(7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)carbamate:To a solution of 7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine (150 mg,0.65 mmol) and tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (152 mg,0.71 mmol) in DMA (2.0 mL) was added N,N-diisopropylethylamine. Thereaction mixture was heated to 160° C. in a microwave reactor for onehour. The cooled reaction mixture was diluted with water and extracted3× with EtOAc. The combined organic layers were washed with saturatedaqueous ammonium chloride and brine, then dried over sodium sulfate,isolated by vacuum filtration, and concentrated in vacuo. The resultingoil was purified by silica gel column chromatography (eluent:EtOAc/hexanes) to provide the desired material.

ES/MS: 410.90, 412.04 [M+H⁺].

tert-butyl((1S,2R)-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)carbamate(I-14): A microwave vial was charged with tert-butyl((1S,2R)-2-((7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)carbamate(150 mg, 0.37 mmol), bis(pinacolato)diboron (149 mg, 0.59 mmol),trans-dichlorobis(triphenylphosphine)palladium (II) (12.9 mg, 0.018mmol), and potassium acetate (109 mg, 1.11 mmol). Dioxane (0.82 mL) andDMF (0.4 mL) were added, and the reaction mixture was degassed bybubbling argon through the mixture for 60 seconds. The vial was sealed,and the reaction mixture was heated at 150° C. in a microwave reactorfor 20 minutes. The reaction mixture was filtered, and the filtrate wasconcentrated and purified by silica gel column chromatography (eluent:EtOAc/hexanes) to provide I-14. Mass fragmentation provided the mass ofthe boronic acid.

ES/MS: 376.21 [M+H⁺]. Preparation of Intermediates I-15:

N-((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-2-hydroxy-2-methylpropanamide(I-15): To a solution of 2-hydroxyisobutyric acid (35.2 mg, 0.34 mmol)and HATU (128 mg, 0.34 mmol) in MeCN (0.5 mL) was addedN,N-diisopropylethylamine (0.12 mL, 0.65 mmol). The mixture was stirredfor 5 minutes, then a solution of(1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-aminehydrochloride (100 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.16mL, 0.92 mmol) in MeCN (0.5 mL) was added. Upon completion, the reactionmixture was concentrated and purified by silica gel columnchromatography (eluent: MeOH/DCM) to provide I-15.

ES/MS: 375.44, 377.07 [M+H⁺]. Preparation of Intermediate I-16:

N-(2-azabicyclo[2.2.2]octan-4-yl)acetamide hydrochloride: To a solutionof tert-butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (200 mg,0.88 mmol) in DCM (2.0 mL) was added triethylamine (0.25 mL, 1.77 mmol)followed by acetic anhydride (92 μL, 0.97 mmol). The reaction mixturewas stirred for 30 minutes, then concentrated in vacuo. To the resultingoil was added HCl (4M in 1,4-dioxane, 2.2 mL, 8.8 mmol). The suspensionwas stirred at 40° C. for 2 hours, then concentrated and used withoutadditional purification.

N-(2-(5-bromo-1,3,4-thiadiazol-2-yl)-2-azabicyclo[2.2.2]octan-4-yl)acetamide(I-16): To a crude suspension ofN-(2-azabicyclo[2.2.2]octan-4-yl)acetamide hydrochloride (132 mg, 0.65mmol) in dioxane (2 mL) was added 2,5-dibromo-1,3,4-thiadiazole (75.0mg, 0.31 mmol) followed by N,N-diisopropylethylamine (0.27 mL, 1.5mmol). The reaction mixture was heated at 120° C. for 1 hour. The cooledreaction mixture was concentrated in vacuo and purified by silica gelcolumn chromatography (eluent: MeOH/DCM) to provide I-16.

ES/MS: 331.19, 333.10 [M+H⁺].

The following intermediates were synthesized as described for I-16 usingthe appropriate starting amine:

Preparation of Intermediate I-17:

2-azaspiro[3.5]nonan-7-one hydrochloride: Tert-butyl7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (150 mg, 0.63 mmol) was takenin HCl (4M in 1,4-dioxane, 1.6 mL, 6.27 mmol) and heated at 40° C. for30 minutes. The reaction mixture was concentrated and used withoutpurification.

2-(5-bromo-1,3,4-thiadiazol-2-yl)-2-azaspiro[3.5]nonan-7-one: To asuspension of crude 2-azaspiro[3.5]nonan-7-one hydrochloride (110 mg,0.63 mmol) in dioxane (2.0 mL) was added 2,5-dibromo-1,3,4-thiadiazole(125 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.56 mmol).The reaction mixture was heated at 120° C. for one hour, thenconcentrated in vacuo and used without purification.

2-(5-bromo-1,3,4-thiadiazol-2-yl)-7-methyl-2-azaspiro[3.5]nonan-7-ol(I-17): To a solution of crude2-(5-bromo-1,3,4-thiadiazol-2-yl)-2-azaspiro[3.5]nonan-7-one (155 mg,0.51 mmol) in THF (1.0 mL) at 0° C. was added methylmagnesium bromide(3M in diethyl ether, 0.26 mL, 0.77 mmol). The reaction mixture waswarmed to RT and stirred for one hour. The reaction mixture was quenchedwith saturated aqueous sodium bicarbonate and extracted with threeportions of EtOAc. The combined organic layers were dried over sodiumsulfate, isolated by filtration, concentrated in vacuo and purified bysilica gel column chromatography (eluent: MeOH/DCM) to provide I-17.

ES/MS: 318.09, 320.06 [M+H⁺]. Preparation of Intermediate I-18:

2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-bromo-1,3,4-thiadiazole: Asolution of tert-butyl3-(5-bromo-1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate(synthesized following the protocol for I-11 using the appropriateamine) (150 mg, 0.42 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (2.2 mL,20.8 mmol) was heated in a microwave reactor 30 minutes at 150° C. Thecooled reaction was concentrated in vacuo to provide the desired productwhich was used without purification.

ES/MS: 261.05, 263.02 [M+H⁺].

1-(3-(5-bromo-1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-hydroxy-2-methylpropan-1-one(I-18): To a solution of crude2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-bromo-1,3,4-thiadiazole (108mg, 0.42 mmol) and 2-hydroxy-2-methylpropanoic acid (56.2 mg, 0.54 mmol)in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.30 mL, 1.66 mmol)followed by a solution of HATU (237 mg, 0.62 mmol) in DMF (0.5 mL). Thereaction mixture was stirred at RT for 15 minutes, then concentrated invacuo and partitioned between water and EtOAc. The aqueous later wasextracted two additional times with EtOAc, and the combined organiclayers were dried over sodium sulfate, isolated by filtration,concentrated in vacuo, and purified by silica gel column chromatography(eluent: MeOH/DCM) to provide I-18.

ES/MS: 347.04, 349.03 [M+H⁺]. Preparation of Intermediate I-19:

1-(3-(5-bromo-1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)ethan-1-one(I-19): To a solution of crude2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-bromo-1,3,4-thiadiazole (41.9mg, 0.16 mmol) in DCM (3.2 mL) was added triethylamine (92 μL, 0.66mmol) followed by acetic anhydride (16.7 μL, 0.18 mmol). The reactionmixture was stirred at RT for 30 minutes then concentrated in vacuo andpurified by silica gel column chromatography (eluent: MeOH/DCM) toprovide I-19.

ES/MS: 303.15, 305.08 [M+H⁺].

The following intermediates were synthesized as described for I-19 usingthe appropriate amine and the appropriate anhydride, acid chloride,chloroformate, or sulfonyl chloride:

Preparation of Intermediate I-20:

(±) methyltrans-2-(2-formylhydrazine-1-carbonyl)cyclopropane-1-carboxylate: To asuspension of racemic trans-2-methoxycarbonylcyclopropanecarboxylic acid(2 g, 13.9 mmol) and N-methylmorpholine (1.68 mL, 15.3 mmol) in THF (50mL) at 0° C. was added isobutyl chloroformate (1.98 mL, 15.3 mmol)dropwise. The suspension was stirred for 15 minutes at 0° C., and thenformohydrazide (917 mg, 15.3 mmol) was added in one portion. Thesuspension was stirred for 10 minutes at 0° C., and was then stirred for30 minutes at room temperature. Methanol (10 mL) was added to thereaction mixture, and slurry was filtered, rinsing with methanol. Thefiltrate was concentrated and used without further purification.

ES/MS: 187.009 (M+H⁺)

(±) methyl trans-2-(1,3,4-thiadiazol-2-yl)cyclopropane-1-carboxylate(±I-20):

To a solution of methyl (1 S,2S)-2-(2-formylhydrazine-1-carbonyl)cyclopropane-1-carboxylate (2 g, 10.7mmol) in THF (50 mL) at 65° C. was added Lawesson's Reagent (6.52 g,16.1 mmol) in one portion. The reaction was stirred at 65° C. for 20minutes, until conversion of the starting material to desired productwas observed by LCMS. The flask was cooled, and diluted with EtOAc (100mL). The organic layer was washed with water (50 mL). The aqueous layerwas back-extracted with EtOAc (2×50 mL), and the combined organic layerswere dried over MgSO4, filtered, and concentrated under reducedpressure. The crude material was purified twice by silica gelchromatography (eluent EtOAc/hexanes followed by methanol/EtOAc) to give±I-20 as a clear viscous oil.

ES/MS: 185.023 [M+H]⁺

1H NMR (400 MHz, Methanol-d4) δ 9.32 (s, 1H), 3.76 (s, 3H), 3.13-2.98(m, 1H), 2.41 (ddd, J=8.8, 5.7, 4.0 Hz, 1H), 1.76 (dddd, J=19.3, 8.8,6.0, 4.5 Hz, 2H).

Preparation of Intermediates I-21:

2-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-thiadiazole (I-21): To asolution of 2-(piperidin-4-yl)-1,3,4-thiadiazole hydrochloride(synthesized as described for I-1 using the appropriate carboxylic acid)(200 mg, 0.97 mmol) in CH₂Cl₂ (5 mL) was added N,N-Diisopropylethylamine(0.17 mL, 0.97 mmol). The mixture was cooled to 0° C., and thenoxetan-3-one (0.14 g, 1.94 mmol) was added, followed by sodiumtriacetoxyborohydride (618 mg, 2.92 mmol). The mixture was stirred undernitrogen for 90 minutes, upon which time conversion of the startingmaterial to desired product was observed by LCMS. The reaction wasquenched with 5 drops of sat. aq. NaHCO₃, and the crude reaction wasdry-loaded onto silica. The crude material was purified by silica gelchromatography (eluent EtOAc/hexanes followed by methanol/EtOAc) to giveI-21.

ES/MS: 226.178 [M+H]⁺ Preparation of Intermediate I-22:

(1R,5S,8r)-3-benzyl-8-methyl-3-azabicyclo[3.2.1]octan-8-ol (I-22): To anoven-dried 250 mL round bottom flask was added3-benzyl-3-azabicyclo[3.2.1]octan-8-one (3 g, 13.9 mmol), and the flaskwas placed under an N₂ atmosphere. THF (100 mL) was added, and thesolution was cooled to −78° C. MeMgBr (3M in ether, 13.9 mL, 41.8 mmol)was added dropwise, and the reaction was stirred 30 min at −78° C. LCMSaliquot showed conversion to desired product. 10 mL sat. aq. ammoniumchloride was added dropwise, and the mixture was allowed to warm to RT.The mixture was diluted with 200 mL EtOAc and 50 mL water, and thelayers separated. The aq. layer was extracted twice with 50 mL EtOAc,and the combined organic layers were dried over MgSO4, filtered, andconcentrated. The crude material was purified by silica gelchromatography (eluent EtOAc/hexanes) to give I-22.

ES/MS: 232.390 [M+H]⁺

1H NMR (400 MHz, Chloroform-d) δ 7.40-7.22 (m, 5H), 3.57 (s, 2H), 2.69(d, J=10.6 Hz, 2H), 2.53-2.44 (m, 2H), 1.82 (dt, J=8.0, 2.2 Hz, 2H),1.69 (d, J=4.1 Hz, 4H), 1.29 (s, 3H).

Preparation of Intermediate I-23:

(1R,5S,8r)-8-methyl-3-azabicyclo[3.2.1]octan-8-ol: To a 25 mL roundbottom flask was added I-22 (0.75 g, 3.24 mmol) and ethanol (10 mL). Pdon carbon (10% wt, 0.1 g) was added in one portion, and the mixture wasdegassed with H₂ before stirring overnight under an H₂ atmosphere. LCMSshowed complete conversion to the desired product, and the mixture wasdegassed with argon. The mixture was filtered over celite to remove thesolids, rinsing with EtOH. The filtrate was concentrated, and useddirectly for next step.

ES/MS: 142.189 [M+H]⁺

(1R,5S,8r)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-8-methyl-3-azabicyclo[3.2.1]octan-8-ol(I-23): To a solution of 2,5-dibromo-1,3,4-thiadiazole (777 mg, 3.19mmol) and (1R,5S,8r)-8-methyl-3-azabicyclo[3.2.1]octan-8-ol (450 mg,3.19 mmol) in DMF (2.0 mL) was added N,N-diisopropylethylamine (1.11 mL,6.37 mmol). The reaction mixture was stirred at 120° C. in a sealed vialfor one hour. The cooled reaction mixture was diluted with EtOAc (50mL), and washed twice with water (15 mL). The organic layer was driedover MgSO₄, filtered, concentrated under reduced pressure, and purifiedby silica gel column chromatography (eluent: EtOAc/hexanes) to provideI-23.

ES/MS: 304.309 [M+H⁺].

Preparation of Intermediate I-24:

N-((1R,5S,8s)-3-benzyl-8-methyl-3-azabicyclo[3.2.1]octan-8-yl)acetamide:To a 250 mL round bottomed flask was added3-benzyl-8-methyl-3-azabicyclo[3.2.1]octan-8-ol (1-22) (2 g, 8.65 mmol)and acetonitrile (15 mL), and the solution was then cooled to 0° C.Concentrated Sulfuric acid (12 mL) was added dropwise, and the reactionwas warmed to RT and stirred overnight. The reaction mixture was pouredinto ice, and the resulting solution was adjusted (carefully) to pH 10with sat. aq. KOH. Significant precipitates appeared. Mixture extractedwith EtOAc (3×200 mL), and organic layers were dried over MgSO₄,filtered, and concentrated. The crude material purified by silica gelcolumn chromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc) toprovide the product.

ES/MS: 273.250 [M+H]⁺

1H NMR (400 MHz, Chloroform-d) δ 7.38-7.19 (m, 5H), 5.11 (s, 1H), 3.56(s, 2H), 2.61-2.49 (m, 4H), 2.29 (s, 2H), 1.94 (s, 3H), 1.89-1.74 (m,4H), 1.53 (s, 3H).

N-((1R,5S,8s)-8-methyl-3-azabicyclo[3.2.1]octan-8-yl)acetamide: To a 25mL round bottom flask was addedN-((1R,5S,8s)-3-benzyl-8-methyl-3-azabicyclo[3.2.1]octan-8-yl)acetamide(0.14 g, 0.514 mmol) and ethanol (6 mL). Pd on carbon (10% wt, 55 mg)was added in one portion, and the mixture was degassed with H2 beforestirring overnight under an H₂ atmosphere. LCMS showed completeconversion to the desired product, and the mixture was degassed withargon. The mixture was filtered over celite to remove the solids,rinsing with EtOH. The filtrate was concentrated, and used directly fornext step.

ES/MS: 183.203 [M+H]⁺

N-((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-8-methyl-3-azabicyclo[3.2.1]octan-8-yl)acetamide(I-24): To a solution of 2,5-dibromo-1,3,4-thiadiazole (132 mg, 0.543mmol) and N-((1R,5S,8s)-8-methyl-3-azabicyclo[3.2.1]octan-8-yl)acetamide(90 mg, 0.494 mmol) in 1,4-dioxane (0.5 mL) was addedN,N-diisopropylethylamine (0.22 mL, 1.23 mmol). The reaction mixture wasstirred at 120° C. in a sealed vial for one hour. The cooled reactionmixture was concentrated under reduced pressure, and purified by silicagel column chromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc) toprovide I-24.

ES/MS: 345.151 [M+H⁺].

1H NMR (400 MHz, Chloroform-d) δ 5.20 (s, 1H), 3.61-3.43 (m, 4H),2.66-2.55 (m, 2H), 2.04-1.90 (m, 5H), 1.73-1.65 (m, 2H), 1.62 (s, 3H).

Preparation of Intermediates I-25 and I-26:

Exo-N-((1R,5S,9r)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.3.1]nonan-9-yl)acetamide(I-SEA6) andEndo-N-((1R,5S,9s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.3.1]nonan-9-yl)acetamide(I-26): To a solution of 2,5-dibromo-1,3,4-thiadiazole (250 mg, 1.02mmol) and tert-butyl N-(3-azabicyclo[3.3.1]nonan-9-yl)carbamate (246 mg,1.02 mmol) in 1,4-dioxane (1 mL) was added N,N-Diisopropylethylamine(0.36 mL, 2.05 mmol). The reaction mixture was stirred at 120° C. in asealed vial for one hour. The cooled reaction mixture was concentratedunder reduced pressure, and purified by silica gel column chromatography(eluent: EtOAc/hexanes) to separate both isomers endo-(I-25) andexo-(I-26). The endo- and exo-isomers were distinguished by 2D NOESYspectroscopy.

I-25: ES/MS: 403.851 [M+H⁺].

1H NMR (400 MHz, Chloroform-d) δ 4.75 (s, 1H), 3.82-3.71 (m, 1H),3.68-3.60 (m, 2H), 3.60-3.45 (m, 2H), 2.19 (s, 2H), 1.99-1.63 (m, 6H),1.47 (s, 9H).

I-26: ES/MS: 403.204 [M+H⁺].

1H NMR (400 MHz, Chloroform-d) δ 4.93 (d, J=7.4 Hz, 1H), 3.95-3.80 (m,3H), 3.56 (dd, J=12.7, 3.5 Hz, 2H), 2.10 (s, 2H), 1.88-1.59 (m, 6H),1.49 (s, 9H).

Preparation of Intermediate I-27:

N-(4-(5-bromo-1,3,4-thiadiazol-2-yl)phenyl)acetamide (I-27): To asuspension of 4-(5-bromo-1,3,4-thiadiazol-2-yl)aniline (200 mg, 1.13mmol) in CH₂Cl₂ (5 mL) and THF (5 mL) at 0° C. was added triethylamine(0.315 mL, 2.26 mmol) followed by acetic anhydride (0.11 mL, 1.13 mmol).The reaction mixture was stirred at RT for 1 hour, followed by 30minutes at 40° C. The reaction was diluted with 20 mL EtOAc, and washedwith 10 mL water. The aqueous layer was extracted with 3×10 mL EtOac,and the combined organic layers were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc) to provide I-27.

ES/MS: 220.113 [M+H⁺]. Preparation of Intermediates I-28 and I-29:

tert-butyl (3R)-3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate: Toan oven-dried 100 mL round bottom flask was added tert-butyl(3S)-3-fluoro-4-oxo-piperidine-1-carboxylate (1 g, 4.6 mmol), and theflask was placed under an N₂ atmosphere. THF (40 mL) was added, and thesolution was cooled to −78° C. MeMgBr (3M in ether, 3.84 mL, 11.5 mmol)was added dropwise, and the reaction was stirred 5 minutes at −78° C.LCMS aliquot showed conversion to desired product. 5 mL Sat. aq.ammonium chloride was added dropwise, and the mixture was allowed towarm to RT. The mixture was diluted with 100 mL EtOAc and 50 mL water,and the layers separated. The aq. layer was extracted twice with 50 mLEtOAc, and the combined organic layers were dried over MgSO4, filtered,and concentrated. The crude material was purified by silica gelchromatography (eluent EtOAc/hexanes) to give the product as adiastereomeric mixture.

ES/MS: 233.69 [M+H]⁺

(3R)-3-fluoro-4-methylpiperidin-4-ol hydrochloride: To a solution oftert-butyl (3R)-3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate(mixture of diastereomers) (1.03 g, 4.42 mmol) in 1,4-dioxane (8 mL) andmethanol (3 mL) was added hydrochloric acid (4M in dioxane, 4.7 mL, 18.7mmol). The reaction mixture was stirred at RT for 4 hours, thenconcentrated under reduced pressure and used without additionalpurification.

ES/MS: 134.129 [M+H⁺].

(3R,4R)-1-(5-bromo-1,3,4-thiadiazol-2-yl)-3-fluoro-4-methylpiperidin-4-ol(I-28) and(3R,4S)-1-(5-bromo-1,3,4-thiadiazol-2-yl)-3-fluoro-4-methylpiperidin-4-ol(I-29): To a solution of 2,5-dibromo-1,3,4-thiadiazole (800 mg, 3.28mmol) and (3R)-3-fluoro-4-methylpiperidin-4-ol hydrochloride (700 mg,4.13 mmol) in DMF (4.0 mL) was added N,N-diisopropylethylamine (1.71 mL,9.84 mmol). The reaction mixture was stirred at 120° C. in a sealed vialfor one hour. The cooled reaction mixture was diluted with EtOAc (50mL), and washed with sat. aq. NH₄Cl (20 mL). The aqueous wasback-extracted three times with EtOAc (20 mL). The combined organiclayers were dried over MgSO₄, filtered, concentrated under reducedpressure, and purified by silica gel column chromatography (eluent:EtOAc/hexanes) to provide a mixture of diastereomers, which were furtherseparated by SFC.

I-28: ES/MS: 296.039 [M+H⁺]. I-29:ES/MS: 296.034 [M+H⁺].

The following intermediates were synthesized as described for I-28 usingtert-butyl (3S)-3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate instep 1:

Preparation of Intermediate I-30:

Endo-7-benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one oxime:7-benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one (2 g, 8.65 mmol),hydroxylamine hydrochloride (900 mg, 13 mmol) and pyridine (1.2 mL, 14.9mmol) in ethanol (20 mL) was heated to 100° C. for 2 hours. The reactionmixture was concentrated under reduced pressure. 2.5 N Aqueous sodiumhydroxide solution (10 mL) was added to the residue. The resultingsolution was extracted 2× with ethyl acetate (50 mL), washed with water,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel (eluent: EtOAc/hexane mixture) to afford the product.

7-benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-amine: To a de-oxygentatedsolution of 7-benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one oxime (1.77 g,7.19 mmol) in ethanol (50 mL) was added Raney nickel (0.6 g, suspensionin water) under an argon atmosphere. The reaction was hydrogenated usinga hydrogen balloon overnight. The reaction was filtered through a bed ofcelite and the filtrate was concentrated to dryness. Care was taken toavoid drying out the filtered nickel catalyst. The crude residue waspurified by flash column chromatography on silica gel (eluent:MeOH/CH₂Cl₂). A mixture of exo-and endo-isomers was obtained.

ES/MS: 233.198 [M+H⁺].

N-(7-benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)acetamide: To asuspension of 7-benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-amine (1.43 g,6.16 mmol) in CH₂Cl₂ (20 mL) at 0° C., was added triethylamine (1.72 mL,12.3 mmol) and then acetic anhydride (0.64 mL, 6.77 mmol). The reactionmixture was stirred at 0° C. for 15 minutes, then diluted with EtOAc (50mL) and sat. aq. NH₄Cl. The layers were separated, and the aqueous layerwas extracted with EtOAc (5×20 mL). the combined organic layers wereconcentrated under reduced pressure and purified by silica gel columnchromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc) to provide theproduct.

ES/MS: 275.267 [M+H⁺].

N-(3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)acetamide: To a 100 mL roundbottom flask was addedN-(7-benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)acetamide (1.35 g, 4.92mmol) and ethanol (20 mL). Pd on carbon (10% wt, 524 mg) was added inone portion, and the mixture was degassed with H2 before stirringovernight under an H₂ atmosphere.

LCMS showed complete conversion to the desired product, and the mixturewas degassed with argon. The mixture was filtered over celite to removethe solids, rinsing with EtOH. The filtrate was concentrated, and useddirectly for next step.

ES/MS: 185.213 [M+H⁺].

Endo-N-(7-(5-bromo-1,3,4-thiadiazol-2-yl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)acetamide(I-30): To a solution of 2,5-dibromo-1,3,4-thiadiazole (1.13 g, 4.64mmol) and N-(3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)acetamide (900 mg, 4.89mmol) in 1,4-dioxane (6 mL) was added N,N-Diisopropylethylamine (1.7 mL,9.77 mmol). The reaction mixture was stirred at 120° C. in a sealed vialfor one hour. The cooled reaction mixture was concentrated under reducedpressure, and purified by silica gel column chromatography (eluent:EtOAc/hexanes) to yield a mixture of endo- and exo-isomers(approximately 1:4 endo:exo). The mixture was further purified by SFC toisolate the endo-isomer 1-30.

ES/MS: 347.079 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 4.15 (d, J=3.0 Hz, 1H), 4.10-4.00 (m,4H), 3.89-3.77 (m, 2H), 3.77-3.67 (m, 2H), 2.06 (s, 3H), 1.97 (q, J=2.2Hz, 2H).

Preparation of Intermediate I-31:

methyl 4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylate:To a solution of trans-4-aminocyclohexane-1-fluoro-1-carboxylic acidmethyl ester hydrochloride (3 g, 14.2 mmol) in THF (50 mL) was addedtriethylamine (4.35 mL, 31.2 mmol) and di-tert-butyl dicarbonate (3.4 g,15.6 mmol) at room temperature. The mixture was stirred at roomtemperature overnight, then poured into saturated aqueous ammoniumchloride (50 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic phases were washed with water and brine, dried overanhydrous MgSO₄ and concentrated under reduced pressure to obtain theproduct. Material was used without further purification.

ES/MS: 233.924 [M+H-^(t)Bu]⁺.

4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylic acid: Toa 250 mL round bottom flask with methyl4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylate (3.9 g,14.2 mmol) was added THF (50 mL), MeOH (10 mL) and water (5 mL). LiOH(1M aq., 42.5 mL, 42.5 mmol) was added, and the mixture was stirredovernight at rt. The mixture was concentrated on the rotovap, anddissolved in EtOAc (100 mL). The mixture was acidified with 50% citricacid, and the layers separated. The aqueous layer was back extractedwith 2×50 mL EtOAc. The combined organic layers were dried over MgSO4,filtered, and concentrated under reduced pressure. Material was usedwithout further purification.

ES/MS: 206.003 [M+H-^(t)Bu]⁺.

tert-butyl(4-fluoro-4-(2-formylhydrazine-1-carbonyl)cyclohexyl)carbamate: To asuspension of4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylic acid(3.6 g, 13.8 mmol) and N-methylmorpholine (1.67 mL, 15.2 mmol) in THF(50 mL) at 0° C. was added isobutyl chloroformate (1.97 mL, 15.2 mmol)dropwise. The suspension was stirred for 20 minutes at 0° C., and thenformohydrazide (1.24 mg, 20.7 mmol) was added in one portion. Thesuspension was stirred for 1 hour at room temperature. Methanol (10 mL)was added to the reaction mixture, and slurry was filtered, rinsing withmethanol. The filtrate was concentrated used without furtherpurification.

ES/MS: 247.979 (M+H -^(t)Bu)⁺

tert-butyl (4-fluoro-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate: To asolution of tert-butyl(4-fluoro-4-(2-formylhydrazine-1-carbonyl)cyclohexyl)carbamate (3.79 g,12.5 mmol) in THF (100 mL) at 65° C. was added Lawesson's Reagent (7.58g, 18.7 mmol) in one portion. The reaction was stirred at 65° C. for 60minutes, until conversion of the starting material to desired productwas observed by LCMS. The flask was cooled, and diluted with EtOAc (100mL). The organic layer was washed with water (50 mL). The aqueous layerwas back-extracted with EtOAc (2×50 mL), and the combined organic layerswere dried over MgSO4, filtered, and concentrated under reducedpressure. The crude material was purified by silica gel chromatography(eluent EtOAc/hexanes followed by methanol/EtOAc) to give the product.

ES/MS: 301.919 (M+H⁺)

4-fluoro-4-(1,3,4-thiadiazol-2-yl)cyclohexan-1-amine hydrochloride: To asolution of tert-butyl(4-fluoro-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate (2.5 g, 8.3mmol) in 1,4-dioxane (20 mL) and methanol (4 mL) was added hydrochloricacid (4M in dioxane, 10 mL, 40 mmol). The reaction mixture was stirredat RT for 1 hour, then overnight at 55° C. The mixture was concentratedunder reduced pressure and used without additional purification.

ES/MS: 202.246 [M+H⁺].

N-(4-fluoro-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide (I-31): To asuspension of 4-fluoro-4-(1,3,4-thiadiazol-2-yl)cyclohexan-1-aminehydrochloride (2.1 g, 8.83 mmol) in CH₂Cl₂ (50 mL) at 0° C., was addedtriethylamine (3.70 mL, 26.5 mmol) and then acetic anhydride (0.835 mL,8.83 mmol). The reaction mixture was stirred at 0° C. for 15 minutes,then diluted with EtOAc (100 mL) and sat. aq. NH₄Cl (30 mL). The layerswere separated, and the aqueous layer was extracted with EtOAc (5×40mL). The combined organic layers were concentrated under reducedpressure and purified by silica gel column chromatography (eluent:EtOAc/hexanes, then MeOH/EtOAc), then by silica gel columnchromatography (eluent: MeOH/EtOAc) to provide the product I-31 as amixture of diastereomers.

ES/MS: 244.045 [M+H⁺].

Preparation of Intermediate I-32:

methyl trans-3-hydroxy-3-methylcyclobutane-1-carboxylate: To a solutiontrans-3-hydroxy-3-methylcyclobutane-1-carboxylic acid (850 mg, 6.53mmol) in methanol (15 mL) was added concentrated sulfuric acid (0.142mL). The mixture was refluxed overnight and then concentrated. Theresidue was dissolved in water (10 mL) and the mixture was extractedwith ethyl acetate (20 mL×2). The combined organic phases were washedwith sat. aq. NaHCO₃ (100 mL), and dried over MgSO₄. Concentration gavethe methyl ester, which was carried forward.

methyltrans-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutane-1-carboxylate:To methyl trans-3-hydroxy-3-methylcyclobutane-1-carboxylate (900 mg,6.24 mmol) in anhydrous DMF (15 mL), was added imidazole (1.27 g, 18.7mmol) and tert-Butyldimethylsilyl chloride (2.82 g, 18.7 mmol). Theresulting mixture was heated at 80° C. overnight. After cooling to roomtemperature, water (20 mL) was added and the aqueous layer was extractedwith ethyl acetate (40 mL×3). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The solid was filtered offand the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography, (eluent: EtOAc/hexanes)

ES/MS: 258.948 [M+H⁺]

trans-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutane-1-carboxylicacid: To a 50 mL round bottom flask was added methyltrans-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutane-1-carboxylate(1.36 g, 5.26 mmol) and dissolved in MeOH (15 mL) and water (1 mL).Solid LiOH (378 mg, 15.8 mmol) was added, and the mixture was stirredovernight at 50° C. Most of the methanol was evaporated under reducedpressure, and the residue was dissolved in EtOAc (100 mL). The mixturewas acidified with 50% aq. citric acid, and the layers were separated.The aq layer was extracted 2×50 mL EtOAc. The combined organic layerswere dried over MgSO₄, filtered, and concentrated under reducedpressure. The material was carried forward without further purification.

ES/MS: 245.133 [M+H⁺]

N-[[3-[tert-butyl(dimethyl)silyl]oxy-3-methyl-cyclobutanecarbonyl]amino]formamide:To a suspension oftrans-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutane-1-carboxylicacid (1.17 g, 4.79 mmol) and N-methylmorpholine (0.579 mL, 5.27 mmol) in2-MeTHF (15 mL) at 0° C. was added isobutyl chloroformate (0.683 mL,5.27 mmol) dropwise. The suspension was stirred for 20 minutes at 0° C.,and then formohydrazide (575 mg, 9.57 mmol) was added in one portion.The suspension was stirred for 1 hour at room temperature. The resultingslurry was filtered. The filtrate was concentrated used without furtherpurification.

ES/MS: 287.211 (M+H⁺)

2-(trans-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-1,3,4-thiadiazole:To a solution ofN-[[3-[tert-butyl(dimethyl)silyl]oxy-3-methyl-cyclobutanecarbonyl]amino]formamide(1.3 g, 4.54 mmol) in THF (20 mL) at 65° C. was added Lawesson's Reagent(2.75 g, 6.81 mmol) in one portion. The reaction was stirred at 65° C.for 10 minutes, until conversion of the starting material to desiredproduct was observed by LCMS. The flask was cooled, and dry loaded ontosilica. The crude material was purified by silica gel chromatography(eluent EtOAc/hexanes followed by methanol/EtOAc) to give the product.

ES/MS: 285.226 (M+H^('0))

1H NMR (400 MHz, Methanol-d4) δ 9.37 (s, 1H), 3.65 (tt, J=9.7, 8.0 Hz,1H), 2.77-2.59 (m, 2H), 2.59-2.37 (m, 2H), 1.52 (d, J=0.9 Hz, 3H), 0.92(s, 9H), 0.14 (s, 6H).

trans-1-methyl-3-(1,3,4-thiadiazol-2-yl)cyclobutan-1-ol (1-32): To asolution of2-(trans-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-1,3,4-thiadiazole(660 mg, 2.32 mmol) in 2-MeTHF (5 mL) was added TBAF (1M THF, 2.3 mL,2.32 mmol). The reaction was stirred at room temperature overnight.Water (5 mL) was added to the reaction mixture and the resulting mixturewas extracted with ethyl acetate (3×10 mL). The combined organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography (eluent EtOAc/hexanes followed bymethanol/EtOAc) to give the product I-32.

ES/MS: 171.049 (M+H⁺)

1H NMR (400 MHz, Chloroform-d) δ 9.06 (s, 1H), 3.63 (p, J=8.5 Hz, 1H),2.81-2.68 (m, 2H), 2.52 (td, J=9.4, 2.9 Hz, 2H), 1.53 (s, 3H).

Preparation of Intermediate I-33:

N′-formyl-1,4-dioxaspiro[4.5]decane-8-carbohydrazide: To a suspension of1,4-dioxaspiro[4.5]decane-8-carboxylic acid (0.8 g, 4.3 mmol) andN-methylmorpholine (0.496 mL, 4.51 mmol) in THF (15 mL) at 0° C. wasadded isobutyl chloroformate (0.585 mL, 4.51 mmol) dropwise. Thesuspension was stirred for 30 minutes at 0° C., and then formohydrazide(387 mg, 6.44 mmol) was added in one portion. The suspension was stirredfor 30 minutes at room temperature. The resulting slurry was filtered.The filtrate was concentrated used without further purification.

ES/MS: 229.032 (M+H⁺)

2-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3,4-thiadiazole (I-33): To asolution of N′-formyl-1,4-dioxaspiro[4.5]decane-8-carbohydrazide (0.9 g,3.94 mmol) in THF (20 mL) at 65° C. was added Lawesson's Reagent (1.91g, 4.73 mmol) in one portion. The reaction was stirred at 65° C. for 20minutes, until conversion of the starting material to desired productwas observed by LCMS. The flask was cooled, and dry loaded onto silica.The crude material was purified twice by silica gel chromatography(eluent EtOAc/hexanes followed by methanol/EtOAc) to give the productI-33.

ES/MS: 227.118 (M+H⁺)

Preparation of Intermediate I-34:

2-chloro-5-iodo-N-(oxetan-3-yl)pyridin-4-amine: To a solution of2-chloro-4-fluoro-5-iodo-pyridine (750 mg, 2.91 mmol) and oxetan-3-amine(4.23 g, 68.0 mmol) in NMP (4.0 mL) was added N,N-diisopropylethylamine(319 mg, 4.37 mmol). The reaction mixture was heated in a microwave at150° C. for 60 minutes, then cooled and diluted with EtOAc (50 mL) andwater (10 mL). The resulting mixture was extracted with ethyl acetate(4×20 mL). The combined organic extracts were washed with brine, driedover MgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography (eluentEtOAc/hexanes) to give the product

ES/MS: 311.183 (M+H⁺)

5-(5-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3,4-thiadiazol-2-yl)-2-chloro-N-(oxetan-3-yl)pyridin-4-amine:To a vial was added 2-chloro-5-iodo-N-(oxetan-3-yl)pyridin-4-amine (250mg, 0.805 mmol), 2-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3,4-thiadiazole(I-33) (219 mg, 0.0.966 mmol), Pd(OAc)₂ (45 mg, 0.2 mmol), Xantphos (234mg, 0.4 mmol), copper(I) iodide (92 mg, 0.48 mmol), and cesium carbonate(787 mg, 2.4 mmol). 1,4-Dioxane (3 mL), was added, and the mixture wasdegassed with argon for 1 minute. The vial was sealed and stirred 1 hourat 105° C. Afterward, the vial was cooled, and purified by silica gelchromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc) to yield theproduct.

ES/MS: 409.199 (M+H⁺)

4-(5-(6-chloro-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexan-1-one:To a vial with5-(5-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3,4-thiadiazol-2-yl)-2-chloro-N-(oxetan-3-yl)pyridin-4-amine(159 mg, 0.389 mmol) was added acetonitrile (5 mL) and HCl (1N aq, 2 mL,2 mmol). The reaction was stirred for 4 hours at RT, then diluted withEtOAc (40 mL), and neutralized with sat. aq. NaHCO₃. The layers wereseparated, and the aqueous layer was extracted twice with 20 mL EtOAc.The combined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc) toprovide the product.

ES/MS: 365.131 (M+H⁺)

4-(5-(6-chloro-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-1-methylcyclohexan-1-ol(1-34): To an oven-dried vial was added4-(5-(6-chloro-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexan-1-one(110 mg, 0.3 mmol), and the flask was placed under an N₂ atmosphere. THF(5 mL) was added, and the solution was cooled to −78° C. MeMgBr (3M inether, 0.4 mL, 1.2 mmol) was added dropwise, and the reaction wasstirred 15 minutes at −78° C. LCMS aliquot showed conversion to desiredproduct. 5 mL Sat. aq. ammonium chloride was added dropwise, and themixture was allowed to warm to RT. The mixture was diluted with 30 mLEtOAc and 5 mL water, and the layers separated. The aq. layer wasextracted twice with 10 mL EtOAc, and the combined organic layers weredried over MgSO₄, filtered, and concentrated. The crude material waspurified by silica gel chromatography (eluent EtOAc/hexanes, thenMeOH/EtOAc) to afford both separable isomers of the product I-34.

Isomer 1: ES/MS: 381.167 [M+H]⁺ Isomer 2: ES/MS: 381.207 [M+H]⁺Preparation of Intermediate I-35:

N-((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-N-methylacetamide(I-35): To a solution ofN-((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide(50 mg, 0.15 mmol) in THF (1.5 mL) was added sodium hydride (5 mg, 0.22mmol). Gas evolution was observed and the resulting mixture stirred atroom temperature for 5 minutes before iodomethane (0.011 mL, 0.18 mmol)was added. The reaction was stirred at room temperature for 3 daysbefore additional sodium hydride (5 mg, 0.22 mmol) and iodomethane(0.011 mL, 0.18 mmol) was added. Upon completion, the reaction mixturewas poured into water/NH₄Cl and extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered and concentrated. Theresulting crude residue was purified by silica gel chromatography(eluent: MeOH/CH₂Cl₂) to give I-35.

ES/MS: 345.160 [M+H]⁺ Preparation of Intermediate I-36:

2-Chloroethyl((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate:To a solution of(1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-aminehydrochloride (150 mg, 0.46 mmol) in THF (4.5 mL) was added potassiumcarbonate (190 mg, 1.37 mmol) and 2-chloroethyl chloroformate (98 mg,0.68 mmol). The resulting slurry was stirred at room temperature for 2days. Additional 2-chloroethyl chloroformate (98 mg, 0.68 mmol) wasadded and stirred for 4.5 hours. The reaction was filtered throughcelite, washed with EtOAc, and concentrated to dryness. The resultingcrude residue was purified by silica gel chromatography (eluent:EtOAc/Hexanes) to give the desired product.

ES/MS: 395.900 [M+H]⁺

3-((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)oxazolidin-2-one(I-36): To a solution of 2-Chloroethyl((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(24.5 mg, 0.062 mmol) in MeOH (0.75 mL) was added sodium methoxide(0.023 mL, 0.10 mmol). After stirring at room temperature for 3 days,the reaction was concentrated and dissolved in EtOAc. The organic layerwas washed with NH₄Cl/H₂O, dried over MgSO_(4,) and concentrated. Theresulting crude residue was purified by silica gel chromatography(eluent: MeOH/CH₂Cl₂) to give I-36.

ES/MS: 359.160 [M+H]⁺ Preparation of Intermediate I-37:

(1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(pyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-amine(I-37): To a solution of(1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-aminehydrochloride (25 mg, 0.077 mmol) in NMP (0.4 mL) was added2-chloropyridine (19 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.07mL, 0.40 mmol). The reaction was sealed and heated in a microwave to150° C. for 30 min. The reaction mixture was purified by RP-HPLC(eluent: water/MeCN*0.1% TFA). The resulting product fractions werecombined and concentrated to dryness. The residue was dissolved inCH₂Cl₂ and washed with aqueous bicarbonate. The aqueous layer wasback-extracted with CH₂Cl₂ and the combined organic layers were driedover MgSO₄ and concentrated to give I-37.

ES/MS: 367.210 [M+H]⁺ Preparation of Intermediate I-38:

(1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(pyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-amine(I-38): To a solution of(1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-aminehydrochloride (75 mg, 0.23 mmol) in NMP (1.2 mL) was added2,3-difluoropyridine (82 mg, 0.71 mmol) and N,N-diisopropylethylamine(0.2 mL, 1.15 mmol). The reaction was sealed and heated 120° C. for 4days. The reaction mixture was purified by RP-HPLC (eluent:water/MeCN*0.1% TFA). The resulting product fractions were combined andconcentrated to dryness. The residue was dissolved in CH₂Cl₂ and washedwith aqueous bicarbonate. The aqueous layer was back-extracted withCH₂Cl₂ and the combined organic layers were dried over MgSO₄ andconcentrated to give I-38.

ES/MS: 384.349 [M+H]⁺ Preparation of Intermediate I-39:

1-(5-bromo-1,3,4-thiadiazol-2-yl)piperidine-4-carboxylic acid: To asolution of methyl1-(5-bromo-1,3,4-thiadiazol-2-yl)piperidine-4-carboxylate (22 mg, 0.073mmol) in MeOH (0.15 mL) and THF (0.3 mL) was added aqueous lithiumhydroxide (1M, 0.15 mL, 0.15 mmol). The resulting solution was stirredat room temperature for 3 days. The mixture was concentrated to drynessand used crude in the next step.

ES/MS: 292.095 [M+H]⁺

1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-methylpiperidine-4-carboxamide(I-39): To a solution of1-(5-bromo-1,3,4-thiadiazol-2-yl)piperidine-4-carboxylic acid (21 mg,0.72 mmol) in DMF (0.3 mL) was added a THF solution of methylamine (2M,0.35 mL, 0.7 mmol), HATU (33 mg, 0.087 mmol), andN,N-diisopropylethylamine (0.1 mL, 0.57 mmol). The reaction was stirredat room temperature for 1.5 h and concentrated to dryness. The resultingcrude residue was purified by silica gel chromatography (eluent:MeOH/CH₂Cl₂) to give I-39.

ES/MS: 305.137 [M+H]⁺ Preparation of Intermediate I-40:

Tert-butyl(4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohex-3-en-1-yl)carbamate (I-40):To a solution of tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate(100 mg, 0.31 mmol) in dioxane (1.5 mL) was added2,5-dibromo-1,3,4-thiadiazole (150 mg, 0.62 mmol),Tetrakis(triphenylphosphine)palladium (36 mg, 0.031 mmol), and aqueoussodium carbonate (2M, 0.3 mL, 0.6 mmol). The resulting slurry wasdegassed with argon for 2 min, sealed, and heated in a microwave at 150°C. for 2.5 hours. The resulting mixture was filtered through celite andwashed with ethyl acetate. The combine filtrates were concentrated todryness. The crude residue was dissolved in DMF and purified by RP-HPLC(eluent: water/MeCN*0.1% TFA) to yield I-40 as a trifluoroacetate salt.

ES/MS: 360.003 [M+H]⁺ Preparation of Intermediate I-41:

N-((1s,4s)-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)-2-hydroxy-2-methylpropanamide(I-41): To a slurry of(1s,4s)-4-(1,3,4-thiadiazol-2-yl)cyclohexan-1-amine hydrochloride (100mg, 0.46 mmol) in DMF (1 mL) was added 2-Hydroxyisobutyric acid (60.0mg, 0.576 mmol), HATU (190 mg, 0.5 mmol), and N,N-diisopropylethylamine(0.4 mL, 2.3 mmol). The reaction was stirred at room temperature for 16h and concentrated to dryness. The resulting crude residue was purifiedby silica gel chromatography (eluent: MeOH/CH₂Cl₂) to give I-41.

ES/MS: 270.302 [M+H]⁺ Preparation of Intermediate I-42:

(S)-(1-(5-bromo-1,3,4-thiadiazol-2-yl)pyrrolidin-2-yl)methanol (1-42):To a solution of methyl(2S)-1-(5-bromo-1,3,4-thiodiazol-2-yl)pyrrolidine-2-carboxylate (64.74mg, 0.221 mmol) in tetrahydrofuran (0.55 mL), lithium chloride (28.2 mg,0.664 mmol) and sodium borohydride (25.1 mg, 0.664 mmol) were added atrt followed by addition of ethanol (1 mL), and the mixture was stirredat the same temperature as above for 24 hours. Water (0.5 mL) wascarefully added thereto, and the mixture was concentrated under reducedpressure. Purified on silica using 30%-100% Hexanes/EtOAc, then flushedwith 100% MeOH. Compound containing fractions were concentrated to yieldI-42.

ES/MS: 264.32, 266.03 [M+H⁺]. Preparation of Intermediate I-43:

(S)-1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-methylpyrrolidine-2-carboxamide(I-43): To a solution of methyl(2S)-1-(5-bromo-1,3,4-thiodiazol-2-yl)pyrrolidine-2-carboxylate (38.0mg, 0.130 mmol) in methanol (0.650 mL), methylamine hydrochloride (13.2mg, 0.195 mmol) was added at rt. The mixture was stirred at the sametemperature as above for 24 hours. Saturated sodium bicarbonate solution(5 mL) was carefully added and the mixture was extracted twice with 10mL of EtOAc, washed with 5 mL Brine, and dried over MgSO₄. The mixturewas filtered and concentrated under reduced pressure to provide I-43which was used without additional purification.

ES/MS: 294.08 [M+H+]. Preparation of Intermediate I-44:

2-hydroxy-2-methyl-N-[4-(1,3,4-thiadiazol-2-yl)-1-bicyclo[2.1.1]hexanyl]propenamide(I-44): To a solution of crude4-(1,3,4-thiadiazol-2-yl)bicyclo[2.1.1]hexan-1-amine;hydrochloride (45.0mg, 0.207 mmol) and 2-hydroxy-2-methyl-propanoic acid (23.7 mg, 0.227mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.118 mL,0.661 mmol) followed by the addition of a solution of HATU (82.5 mg,0.217 mmol) in DMF (0.5 mL). The reaction mixture was stirred at RTovernight then directly purified by RP-HPLC (eluent: water/MeCN*0.1%TFA) to yield I-44 as a trifluoroacetate salt.

ES/MS: 268.2 [M+H]⁺ Preparation of Intermediate I-45:

tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)carbamate:4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yltrifluoromethanesulfonate (3.52 g, 10.2 mmol),1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.11 g, 12.7 mmol), Pd(OAc)₂ (0.11 g, 0.51 mmol),butyldi-1-adamantylphosphine (0.37 g, 1.02 mmol), and K₂CO₃ (2.82 g,10.4 mmol) were combined in a sealed tube along with DME (20 mL) andwater (10 mL) and the resulting slurry was degassed with argon thenheated at 80° C. for 16 h. The reaction contents were diluted with EtOAc(70 mL), washed with brine (1×15 mL), and dried over MgSO₄. The cruderesidue was then purified via silica gel chromatography (eluent:EtOAc/hexanes) to give the product tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)carbamate.

ES/MS: 258.0 (M+H⁺).

4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexan-1-amine hydrochloride:A suspension of tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)carbamate(0.23 g, 0.75 mmol) in EtOH (15 mL) was degassed with argon and vacuum.Pd/C (10%, 91 mg, 0.086 mmol) was added and the mixture was stirred witha balloon of H₂ overnight. The reaction was filtered over a Celite plug,rinsed with EtOAc and the filtrate was concentrated to give tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)carbamate which wascarried forward without further purification assuming quantitativeyield. To a solution of tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)carbamate (0.24 g,0.75 mmol) in DCM (6 mL) was added HCl (4.0M in dioxane, 3 mL, 12 mmol)and the resulting solution stirred at room temperature for 16 h. Uponcompletion the reaction mixture was concentrated to dryness to give4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexan-1-amine hydrochloride(I-9) which was used without further purification.

ES/MS: 216.1 (M+H⁺).

2-bromo-N-((1r,4r)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)pyridin-4-amine:To a solution of 2-bromo-4-fluoropyridine (0.23 g, 1.29 mmol) in NMP (7mL) was added 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexan-1-aminehydrochloride (0.38 g, 1.51 mmol) and N,N-diisopropylethylamine (0.70mL, 4.02 mmol). The resulting mixture was heated for 1 h at 160° C. in amicrowave after which the reaction contents diluted with EtOAc, washed 3times with 5% aqueous LiCl, dried and concentrated to give a cruderesidue which was purified by normal phase SiO₂ chromatography (eluent:ethyl acetate/hexanes) to give both the cis and trans products. Thetrans product2-bromo-N-((1r,4r)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)pyridin-4-aminewas isolated and carried forward.

ES/MS: 371.3, 373.0 (M+H⁺).

1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J=5.8 Hz, 1H), 7.62 (s, 1H),7.56 (s, 1H), 7.17 (t, J=60.7 Hz, 1H), 6.61 (d, J=2.2 Hz, 1H), 6.38 (dd,J=5.8, 2.2 Hz, 1H), 4.29 (d, J=7.8 Hz, 1H), 3.33 (dtd, J=11.3, 7.6, 3.9Hz, 1H), 2.58 (tt, J=12.0, 3.6 Hz, 1H), 2.28-2.09 (m, 4H), 1.64-1.44 (m,2H), 1.44-1.16 (m, 2H).

7-(5-bromo-4-(((1r,4r)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-45):2-bromo-N-((1r,4r)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)pyridin-4-aminewas elaborated to the final intermediate7-(5-bromo-4-(((1r,4r)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-45) in the same manner as described in steps 2-3 of Preparation ofIntermediate I-2.

ES/MS: 512.14 (M+H⁺). Example Procedures and Compound Examples

The following compounds were made with the procedures herein, using theappropriate starting materials and protecting group chemistry as needed:

Structure # ES/MS m/z Name Procedure

1 505.193 tert-butyl (2-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)ethyl)carbamate 1

2 659.3  N-((1R,4r)-4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(5- (difluoromethyl)-1,3,4- oxadiazol-2-yl)cyclohexyl)amino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)cyclohexyl)acetamide 1

3 529.315 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((3- methyloxetan-3- yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)acetamide 1

4 487.26  7-(5-(5-(2-oxa-7- azaspiro[3.5]nonan-7-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile 2

Procedure 7: Example 5:

7-(5-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 5)

(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol:To a solution of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate(50.0 mg, 0.16 mmol) in THF (0.5 mL) was added lithium borohydride (2Min THF, 80 μL, 0.16 mmol). The reaction mixture was stirred at roomtemperature for 15 minutes, then quenched with a few drops of saturatedaqueous ammonium chloride. The reaction mixture was concentrated invacuo and purified by silica gel column chromatography (eluent:MeOH/DCM) to provide(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol.

ES/MS: 285.1 [M+H⁺].

7-(5-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 5): A solution of(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol(15.3 mg, 0.054 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-8) (20.2 mg, 0.075 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.0 mg,0.013 mmol), and sodium carbonate (2N in water, 54 μL, 0.11 mmol) in1,4-dioxane (0.4 mL) was sparged with argon for 60 seconds, then heatedin a microwave reactor at 125° C. for 20 minutes. Upon cooling, thereaction mixture was filtered and purified by reverse phase highpressure liquid chromatography (eluent: water/MeCN*0.1% TFA) to providethe final compound Example 5.

ES/MS: 392.2 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J=2.2 Hz, 1H), 8.74 (s, 1H),8.68 (d, J=2.2 Hz, 1H), 8.06 (d, J=5.0 Hz, 1H), 7.99 (s, 1H), 7.23 (d,J=5.0 Hz, 1H), 5.05 (s, 2H), 4.30 (hept, J=6.4 Hz, 1H), 1.49 (d, J=6.4Hz, 6H).

Procedure 4: Example 6:

N-(1-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidin-4-yl)acetamide(Example 6)

N-(1-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidin-4-yl)acetamide(Example 6): A solution of7-(5-bromo-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-2) (42.0 mg, 0.12 mmol), bis(pinacolato)diboron (60.5 mg, 0.24 mmol),bis(triphenylphosphine)palladium(II) dichloride (8.4 mg, 0.012 mmol),and potassium acetate (36.0 mg, 0.37 mmol) in 1,4-dioxane (1.2 mL) andDMF (0.4 mL) was sparged with argon for 60 seconds, then heated in amicrowave reactor at 120° C. for 20 minutes. The reaction mixture wascooled, and to the crude mixture was addedN-(1-(5-bromo-1,3,4-thiadiazol-2-yl)piperidin-4-yl)acetamide (I-4, 28.7mg, 0.094 mmol), XPhos Pd G3 (8.4 mg, 0.0099 mmol), potassium phosphatetribasic (75.1 mg, 0.35 mmol), DME (1.3 mL) and water (0.18 mL). Thereaction mixture was sparged with argon for 60 seconds, then heated in amicrowave reactor at 120° C. for 30 minutes. Upon cooling, the reactionmixture was filtered and purified by reverse phase high pressure liquidchromatography (eluent: water/MeCN*0.1% TFA) to provide the finalcompound Example 6.

ES/MS: 502.3 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.2Hz, 1H), 8.47 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.06 (d, J=5.1 Hz, 1H),7.87 (s, 1H), 7.23 (d, J=5.0 Hz, 1H), 4.29 (p, J=6.4 Hz, 1H), 4.09-3.90(m, 3H), 3.52-3.39 (m, 2H), 2.05 (dd, J=12.8, 3.9 Hz, 2H), 1.96 (s, 3H),1.75-1.54 (m, 2H), 1.47 (d, J=6.4 Hz, 6H).

The following compounds were made according to the procedures herein,using the appropriate starting materials and protecting group chemistryas needed:

Structure # ES/MS m/z Name Procedure

 6 502.31 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol- 2-yl)piperidin-4-yl)acetamide 4

 7 453.177 7-(5-(5-(4- aminophenyl)-1,3,4- thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile1

 8 530.268 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)piperidin-4- yl)acetamide 5

 9 459.280 7-(4-(isopropylamino)- 5-(5-(pyrrolidine-1- carbonyl)-1,3,4-thiadiazol-2-yl)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile5

10 516.221 7-(5-(5-(4- acetylpiperazine-1- carbonyl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile 5

11 530.257 5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-N-(3-(piperidin- 1-yl)propyl)-1,3,4-thiadiazole-2- carboxamide 5

12 516.257 (S)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3- yl)acetamide 5

13 516.266 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3- yl)acetamide 5

14 509.240 (R)-5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-N-(2-fluoro-3- hydroxy-3-methylbutyl)-1,3,4- thiadiazole-2- carboxamide 5

15 419.202 5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-N-methl-1,3,4- thiadiazole-2- carboxamide5

Procedure 5: Example 16:

(S)-7-(5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 16)

(S)-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanonea:To a solution of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate(50.0 mg, 0.16 mmol) in MeOH (0.5 mL) was added (S)-3-hydroxypyrrolidine(13 μL, 0.16 mmol). The reaction mixture was heated at 80° C. for 1hour, then concentrated in vacuo and purified by silica gel columnchromatography (eluent: MeOH/DCM) to provide(S)-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanonea.

ES/MS: 368.1 [M+H⁺].

(S)-7-(5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 16): A solution of(S)-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanonea(25.0 mg, 0.068 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(22.0 mg, 0.082 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.0 mg,0.017 mmol), and sodium carbonate (2N in water, 68 μL, 0.14 mmol) in1,4-dioxane (0.57 mL) was sparged with argon for 60 seconds, then heatedin a microwave reactor at 125° C. for 20 minutes. Upon cooling, thereaction mixture was filtered and purified by reverse phase highpressure liquid chromatography (eluent: water/MeCN*0.1% TFA) to providethe final compound Example 16.

ES/MS: 475.3 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.85 (s, 1H), 8.79 (d, J=2.1 Hz, 1H),8.72 (d, J=2.2 Hz, 1H), 8.10 (d, J=5.1 Hz, 1H), 8.02 (s, 1H), 7.26 (d,J=5.1 Hz, 1H), 4.61 (q, J=3.0, 2.1 Hz, 0H), 4.54 (t, J=3.4 Hz, 1H),4.46-4.11 (m, 3H), 3.86 (dt, J=10.2, 5.1 Hz, 1H), 3.77 (d, J=2.9 Hz,1H), 2.27-2.00 (m, 2H), 1.53 (d, J=6.4 Hz, 6H).

The following compounds were made according to the procedures herein,using the appropriate starting materials and protecting group chemistryas needed:

Structure # ES/MS m/z Name Procedure

17 475.249 (R)-7-(5-(5-(3- hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol- 2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile 5

18 475.236 7-(4-(isopropylamino)- 5-(5-(morpholine-4- carbonyl)-1,3,4-thiadiazol-2-yl)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile5

19 419.165 N-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2- yl)acetamide 4

20 498.251 N-((1r,4r)-4-(5-(4- ((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)acetamide 1

21 515.235 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(oxetan-3- ylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide 1

22 473.271 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(methylamino)pyridin- 3-yl)-1,3,4-thiadiazol- 2- yl)cyclohexyl)acetamide1

23 600.266 methyl (((1R,3r)-3-((5- (5-((1r,4R)-4- acetamidocyclohexyl)-1,3,4-thiadiazol-2-yl)- 2-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)pyridin-4- yl)amino)cyclobutyl) methyl)carbamate 1

Procedure 1: Example 24:

N-((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide(Example 24)

N-((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide(Example 24): To a vial was added7-(5-bromo-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-2) (35 mg, 0.098 mmol),N-((1r,40-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide (I-1) (32 mg,0.14 mmol), Pd(OAc)₂ (5.5 mg, 0.024 mmol), Xantphos (28.5 mg, 0.049mmol), copper(I) iodide (9.4 mg, 0.049 mmol), and cesium carbonate (64mg, 0.197 mmol). 1,4-Dioxane (0.5 mL), was added, and the mixture wasdegassed with argon for 1 minute. The vial was sealed and stirred 2hours at 105° C. Afterward, the vial was cooled and the crude materialwas diluted with DMF (0.5 mL). This mixture was filtered, and purifiedby RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product Example 24as a trifluoroacetate salt.

ES/MS: 501.3 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J=2.2 Hz, 1H), 8.74 (s, 1H),8.71 (d, J=2.2 Hz, 1H), 8.10 (d, J=5.1 Hz, 1H), 7.97 (s, 1H), 7.26 (d,J=5.0 Hz, 1H), 4.39-4.29 (m, 1H), 3.83-3.67 (m, 1H), 3.32-3.25 (m, 1H),2.33 (d, J=13.1 Hz, 2H), 2.12 (d, J=12.7 Hz, 2H), 1.97 (s, 3H), 1.82(qd, J=13.0, 3.3 Hz, 2H), 1.57-1.42 (m, 8H).

Procedure 9: Example 25:

7-(4-(isopropylamino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 25)

N′-acetyl-6-chloro-4-(isopropylamino)nicotinohydrazide: A solution of6-chloro-4-(isopropylamino)nicotinic acid (0.2 g, 0.93 mmol),acetohydrazide (138.05 mg, 1.86 mmol), HATU (425.1 mg, 1.12 mmol), andN,N-Diisopropylethylamine (0.41 ml, 2.33 mmol) in DMF (1.8 mL) wasstirred at room temperature for 18 hours. The reaction solution wasdiluted in ethyl acetate and washed three times with aqueous saturatedammonium chloride solution. The organic extract was dried over sodiumsulfate, filtered, and concentrated to giveN′-acetyl-6-chloro-4-(isopropylamino)nicotinohydrazide

ES/MS: 271.279 [M+H⁺].

2-chloro-N-isopropyl-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-4-amine:A suspension ofN′-acetyl-6-chloro-4-(isopropylamino)pyridine-3-carbohydrazide (0.13 g,0.46 mmol) and Lawesson's reagent (0.21 g, 0.51 mmol) in 1,4-dioxane(2.3 mL) was heated at 80° C. for 18 hours in an aluminum heating block.The crude reaction mixture was purified by normal phase silica gelchromatography (eluent: EtOAc/hexanes) to give2-chloro-N-isopropyl-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-4-amine.

ES/MS: 269.145 [M+H⁺].

7-(4-(isopropylamino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 25): A mixture of2-chloro-N-isopropyl-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-4-amine(0.03 g, 0.13 mmol) ,7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-8) (0.05 g, 0.18 mmol), Dichloro 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) (0.02 g, 0.02 mmol) , and Sodium Carbonate solution (aq,2M, 0.13 ml) in 1,4-dioxane (0.6 mL) was degassed with N₂ for 2 mins,then heated at 80 deg for 20 minutes in a microwave reactor. The crudereaction was purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) andfurther purified by normal phase silica gel chromatography (eluent:EtOAc/dichloromethane) to give7-(4-(isopropylamino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 25).

ES/MS: 376.265 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.63-8.55 (m, 1H), 8.52 (s, 1H), 8.32(d, J=2.9 Hz, 1H), 7.84 (t, J=4.5 Hz, 1H), 7.10 (t, J=5.0 Hz, 1H), 5.48(s, 0H), 5.34 (s, 1H), 4.04 (s, 0H), 2.82 (d, J=3.7 Hz, 1H), 2.18 (s,1H), 2.08-1.97 (m, 2H), 1.60 (s, 1H), 1.46-1.40 (m, 3H), 1.29 (s, 1H),0.95-0.82 (m, 2H).

Procedure 8: Example 26:

7-(5-(5-(2-aminoethyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 26)

7-(5-(5-(2-aminoethyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 26): To a solution of tert-butyl(2-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate(Example 31) (obtained as described in Procedure 1) (4.6 mg, 0.0091mmol) in 1,4-dioxane (0.25 mL) was added HCl (4M in 1,4-dioxane, 11.0μL, 0.046 mmol). The reaction mixture was heated to 30° C. for 30minutes, then concentrated in vacuo and purified by reverse phase highpressure liquid chromatography (eluent: water/MeCN*0.1% TFA) to providethe final compound Example 26.

ES/MS: 405.2 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.82-8.63 (m, 3H), 8.07 (d, J=5.3 Hz,2H), 7.24 (d, J=5.0 Hz, 1H), 4.31 (p, J=6.4 Hz, 1H), 3.66-3.55 (m, 4H),1.50 (d, J=6.4 Hz, 6H).

The following compounds were made according to the procedures herein,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Structure # m/z Name Procedure

27 481.3 (R)-7-(5-(5-((2- fluoro-3-hydroxy-3- methylbutyl)amino)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino) pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile 2

28 427.3 7-(5-(5-(1H-pyrazol-1- yl)-1,3,4-thiadiazol- 2-yl)-4-(isopropylamino) pyridin-2-yl)pyrrolo [1,2-b]pyridazine-3- carbonitrile1

Procedure 2: Example 29:

7-(4-(isopropylamino)-5-(5-(pyrrolidin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 29)

7-(4-(isopropylamino)-5-(5-(pyrrolidin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 29): To a microwave vial containing(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)boronicacid (I-3) as a trifluoroacetate salt (10 mg, 0.023 mmol),2-bromo-5-pyrrolidin-1-yl-1,3,4-thiadiazole (6 mg, 0.025 mmol), Pd(OAc)₂(1 mg, 0.0046 mmol), Xantphos (5.3 mg, 0.0092 mmol), and cesiumcarbonate (22.5 mg, 0.069 mmol) was added 1,4-dioxane (0.5 mL). Themixture was degassed with argon for 1 min, sealed, and heated undermicrowave conditions for 20 min at 150° C. Afterward, the vial wascooled and the crude material was diluted with DMF (0.5 mL). Thismixture was filtered, and purified by RP-HPLC (eluent: water/MeCN*0.1%TFA) to yield the product Example 29 as a trifluoroacetate salt.

ES/MS: 341.3 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2Hz, 1H), 8.49 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d,J=5.1 Hz, 1H), 4.37-4.24 (m, 1H), 3.67-3.60 (m, 4H), 2.22-2.15 (m, 4H),1.53-1.43 (m, 6H).

Procedure 6: Example 30:

7-(4-(isopropylamino)-5-(1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 30)

2-chloro-N-isopropyl-5-(1,3,4-thiadiazol-2-yl)pyridin-4-amine: To asolution of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate(50.0 mg, 0.16 mmol) in 1,4-dioxane (2.0 mL) was added potassiumcarbonate (2.4M in water, 0.20 mL, 0.48 mmol). The reaction mixture washeated at 110° C. for 2 hours. The reaction was concentrated andpartitioned between water and EtOAc. The organic layer was isolated, andthe aqueous layer was extracted with two additional portions of EtOAc.The organic layers were combined, dried over sodium sulfate, filtered,and concentrated to provide2-chloro-N-isopropyl-5-(1,3,4-thiadiazol-2-yl)pyridin-4-amine which wasused without additional purification.

ES/MS: 255.1 [M+H⁺].

7-(4-(isopropylamino)-5-(1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 30): A solution of2-chloro-N-isopropyl-5-(1,3,4-thiadiazol-2-yl)pyridin-4-amine (32.0 mg,0.13 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-8) (40.3 mg, 0.15 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.0 mg,0.031 mmol), and sodium carbonate (2N in water, 125 μL, 0.14 mmol) in1,4-dioxane (1.0 mL) was sparged with argon for 60 seconds, then heatedin a microwave reactor at 125° C. for 20 minutes. Upon cooling, thereaction mixture was filtered and purified by reverse phase highpressure liquid chromatography (eluent: water/MeCN*0.1% TFA) to providethe final compound Example 30.

ES/MS: 362.2 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 9.62 (s, 1H), 8.83 (s, 1H), 8.78 (d,J=2.2 Hz, 1H), 8.71 (d, J=2.2 Hz, 1H), 8.10 (d, J=5.0 Hz, 1H), 8.02 (s,1H), 7.26 (d, J=5.1 Hz, 1H), 4.35 (hept, J=6.3 Hz, 1H), 1.53 (d, J=6.4Hz, 6H).

Procedure 3: Example 31:

7-(5-(5-(3-hydroxy-3-methylbutyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 31)

Methyl4-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-4-oxobutanoate:To a solution of known compound6-chloro-4-(isopropylamino)nicotinohydrazide (2 g, 8.75 mmol) indichoromethane (100 mL) was added triethylamine (3.66 mL, 26.2 mmol),and the reaction was cooled to 0° C. To the reaction was added methyl4-chloro-4-oxobutanoate (1.72 mL, 14 mmol) dropwise, and the resultingmixture stirred at room temperature for 5 hours. Afterward, saturatedaqueous NaHCO₃ was added, and layers were separated. The organic layerwas extracted with dichloromethane. The combined organic layers weredried over MgSO₄, filtered and concentrated. The resulting crude residuewas purified by silica gel chromatography (eluent: EtOAc/hexanes, thenMeOH/EtOAc) to give the desired product.

ES/MS: 343.4 [M+H]⁺

Methyl3-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanoate:To a solution of methyl4-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-4-oxobutanoate(710 mg, 2.07 mmol) in THF (50 mL) was added Lawesson's reagent (1.68 g,4.14 mmol) in one portion, and the reaction was stirred at reflux for 90minutes. Afterward, the reaction was cooled, and the mixture was dilutedwith EtOAc, and the organics were washed twice with 50% (by volume)aqueous NaHCO₃. The organic layer was dried over MgSO₄, filtered andconcentrated. The resulting crude residue was purified by silica gelchromatography (eluent: EtOAc/hexanes) to give the desired product.

ES/MS: 341.3 [M+H]⁺

4-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-methylbutan-2-ol:To a flask with methyl3-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanoate(216 mg, 0.63 mmol) under N₂ was added THF (7 mL), and the reaction wascooled to 0° C. To the reaction was added methylmagnesium bromide (3Msolution in Et₂O, 1.48 mL, 4.44 mmol) dropwise, and the reaction wasstirred for 30 min at 0° C. . Afterward, the reaction was quenched bydropwise addition of saturated aqueous NH₄Cl, and the mixture wasdiluted with EtOAc and water. The layers were separated, and the aqueouslayer was washed once with EtOAc. The combined organic layers were driedover MgSO₄, filtered and concentrated. The resulting crude residue waspurified by silica gel chromatography (eluent: EtOAc/hexanes) to givethe desired product.

ES/MS: 341.2 [M+H]⁺

7-(5-(5-(3-hydroxy-3-methylbutyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 31): To a microwave vial was added4-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-methylbutan-2-ol(50 mg, 0.15 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-8) (55 mg, 0.21 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.8 mg,0.029 mmol). To the vial was added DME (1.0 mL) and sodium carbonate (2Msolution in water, 0.15 mL, 0.29 mmol). The mixture was degassed withargon for 1 min, sealed, and heated under microwave conditions for 20min at 120° C. Afterward, the vial was cooled and the mixture wasconcentrated under vacuum. The crude material was diluted with DMF (1mL). This mixture was filtered, and purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product Example 31 as atrifluoroacetate salt.

ES/MS: 448.5 [M+H]⁺

1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J=2.2 Hz, 1H), 8.74-8.71 (m,2H), 8.11 (d, J=5.1 Hz, 1H), 7.97 (s, 1H), 7.26 (d, J=5.1 Hz, 1H), 4.35(hept, J=6.4 Hz, 1H), 3.41-3.35 (m, 2H), 2.12-1.99 (m, 2H), 1.52 (d,J=6.4 Hz, 6H), 1.33 (s, 6H).

The following compounds were made according to the procedures set forthpreviously, using the appropriate starting materials and protectinggroup chemistry as needed:

ES/MS Structure # m/z Procedure Name 32 446.3  2 7-(4-(isopropylamino)-5- (5-(tetrahydro-2H- pyran-4-yl)-1,3,4- thiadiazol-2-yl)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

33 474.45 2 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2- yl)azetidin-3-yl)acetamide

34 614.32 1 methyl ((1R,4r)-4-((5- (5-((1r,4R)-4- acetamidocyclohexyl)-1,3,4-thiadiazol-2-yl)-2- (3-cyanopyrrolo[1,2- b]pyridazin-7-yl)pyridin-4- yl)amino)cyclohexyl) carbamate

35 502.57 2 (S)-7-(5-(5- (hexahydropyrazino [2,1-c][1,4]oxazin-8(1H)-yl)-1,3,4-thiadiazol-2-yl)- 4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

36 502.45 2 (R)-7-(5-(5- (hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)- 1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

37 449.48 1 7-(5-(5-((2-hydroxy-2- methylpropyl)amino)-1,3,4-thiadazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

38 528.40 2 N-((1R,5S,8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1]octan- 8-yl)acetamide

39 528.42 2 N-((1R,5S,8r)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1]octan- 8-yl)acetamide

40 515.36 5 (R)-N-(1-(2-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)thiazole-5- carbonyl)pyrrolidin-3-yl)acetamide

41 530.47 5 (S)-N-((1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-2- yl)methyl)acetamide

42 530.56 5 (R)-N-((1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-2- yl)methyl)acetamide

43 532.45 5 methyl (S)-(1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3- yl)carbamate

44 532.42 5 methyl (R)-(1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3- yl)carbamate

45 514.45 2 N-((1R,5S,6r)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.1.1]heptan- 6-yl)acetamide

46 542.52 5 (S)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3- yl)cyclopropanecarboxamide

47 542.59 5 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3- yl)cyclopropane- carboxamide

48 530.53 5 (S)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)piperidin-3- yl)acetamide

49 530.60 5 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazole-2-carbonyl)piperidin-3- yl)acetamide

Procedure 10: Example 50:

N-((1r,4r)-4-(5-(6-(2-(((1R,2S)-2-aminocyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide(Example 50): Tert-butyl((1S,2R)-2-((7-((5-(5((1r,4r-4-acetamidocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)carbamate(prepared as described in Procedure 1 from the appropriate3-bromo-pyridine and thiadiazole) (39.1 mg, 0.057 mmol) was taken intrifluoroacetic acid (1.0 mL) and stirred at RT for 5 minutes. Thereaction was concentrated and purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product Example 50 as atrifluoroacetate salt.

ES/MS: 589.82 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 9.06 (s, 1H), 8.73 (s, 1H), 7.74 (d,J=5.2 Hz, 1H), 7.71 (s, 1H), 7.08 (d, J=5.1 Hz, 1H), 4.65-4.57 (m, 1H),4.33 (p, J=6.4 Hz, 1H), 3.84-3.68 (m, 1H), 3.63-3.52 (m, 1H), 2.31 (d,J=13.0 Hz, 2H), 2.10 (d, J=12.8 Hz, 2H), 2.06-1.65 (m, 13H), 1.67-1.36(m, 9H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

EMS/MS Structure # m/z Procedure Name

51 601.46 2 methyl (((1R,3r)-3-((2- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-5-(5- ((R)- hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)-1,3,4-thiadiazol-2- yl)pyridin-4-yl)amino)cyclobutyl) methyl)carbamate

52 627.50 2 methyl (((1R,3r)-3-((5- (5-((1R,5S,8S)-8- acetamido-3-azabicyclo[3.2.1]octan- 3-yl)-1,3,4-thiadiazol-2- yl)-2-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-4- yl)amino)cyclobutyl)methyl)carbamate

Procedure 11: Example 53:

N-((1R,5S,8S)-3-(5-(4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide(Example 53)

N-((1R,5S,8s)-3-(5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide:A microwave vial was charged withN-((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide(200 mg, 0.60 mmol),2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(171 mg, 0.66 mmol), palladium(II) acetate (20.3 mg, 0.091 mmol),Xantphos (105 mg, 0.18 mmol), and cesium carbonate (590 mg, 0.18 mmol).Dioxane (3.0 mL) was added, and the reaction mixture was degassed bybubbling argon for 60 seconds. The vial was sealed and heated withstirring at 120° C. for 20 minutes in a microwave reactor. The cooledreaction mixture was filtered through a pad of Celite with EtOAc,concentrated in vacuo, and used without additional purification.

(R)-2-((5-(5-((1R,5S,8S)-8-acetamido-3-azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-2-chloropyridin-4-yl)amino)propenamide:To a solution of crudeN-((1R,5S,8s)-3-(5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide(231 mg, 0.60 mmol) in butyronitrile (3.0 mL) was added D-alaninamidehydrochloride (90.3 mg, 0.73 mmol) and N,N-diisopropylethylamine (0.47mL, 2.7 mmol). The reaction was heated at 130° C. for 45 minutes. Thecooled reaction was concentrated in vacuo and used without additionalpurification.

N-((1R,5S,8S)-3-(5-(6-chloro-4-(((R)-1-cyanoethyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide:A solution of crude(R)-2-((5-(5-((1R,5S,8S)-8-acetamido-3-azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-2-chloropyridin-4-yl)amino)propanamide(272 mg, 0.60 mmol) in THF (3.0 mL) was cooled to 0° C. To the solutionwas added pyridine (0.24 mL, 3.0 mmol) and trifluoroacetic anhydride(0.13 mL, 0.91 mmol). The reaction was allowed to warm to roomtemperature while stirred for 25 minutes. The reaction mixture wasconcentrated in vacuo and purified by silica gel column chromatography(eluent: MeOH/DCM) to provide the desired product.

ES/MS: 432.61 (M+H⁺)

N-((1R,5S,8S)-3-(5-(4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide (Example 53): A microwave vial was chargedwithN-((1R,5S,8S)-3-(5-(6-chloro-4-(((R)-1-cyanoethyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide(84.0 mg, 0.19 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Intermediate I-8, 78.5 mg, 0.29 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (28.9 mg,0.039 mmol). To the flask was added DME (4.0 mL) and a 2M aqueoussolution of sodium carbonate (0.39 mL, 0.78 mmol). The reaction mixturewas degassed by bubbling argon for 60 seconds. The vial was sealed andheated with stirring at 120° C. for 15 minutes in a microwave reactor.The cooled reaction mixture was concentrated and purified by RP-HPLC(eluent: water/MeCN*0.1% TFA) to yield the product Example 53 as atrifluoroacetate salt.

ES/MS: 539.38 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J=2.2 Hz, 1H), 8.72 (d, J=2.1Hz, 1H), 8.64 (s, 1H), 8.14 (d, J=5.1 Hz, 1H), 8.08 (s, 1H), 8.03 (d,J=5.8 Hz, 1H), 7.27 (d, J=5.0 Hz, 1H), 5.26 (q, J=6.9 Hz, 1H), 4.01 (d,J=4.9 Hz, 1H), 3.84 (d, J=12.0 Hz, 2H), 3.57 (d, J=11.9 Hz, 2H), 2.46(s, 2H), 2.08-1.98 (m, 5H), 1.92 (d, J=7.0 Hz, 3H), 1.75-1.64 (m, 2H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z cedure Name

54 641.55 2 methyl ((1R,4r)-4-((5-(5- ((1R,5S,8S)-8-acetamido-3-azabicyclo[3.2.1] octan-3-yl)-1,3,4- thiadiazol-2-yl)-2-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)pyridin- 4-yl)amino)cyclohexyl)carbamate

55 528.61 2 N-((1R,3r,5S)-8-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-8-azabicyclo [3.2.1]octan-3- yl)acetamide

56 528.62 2 N-((1R,3s,5S)-8-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-8-azabicyclo [3.2.1]octan-3-yl) acetamide

57 599.56 2 N-((1R,5S,8s)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1]octan- 8-yl)morpholine-4-carboxamide

58 564.46 2 N-((1R,5S,8s)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1] octan-8-yl)methane- sulfonamide

59 544.56 2 methyl ((1R,5S,8s)-3-(5- (6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1] octan-8-yl)carbamate

60 486.48 2 7-(5-(5-((1R,5S,8s)-8- amino-3- azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)- 4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b] pyridazine-3-carbonitrile

Procedure 12: Example 61:

N-((1R,5S,8S)-3-(5-(6-(2-(((1R,2S)-2-aminocyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(((R)-1-cyanoethyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide(Example 61)

N-((1R,5S,8S)-3-(5-(6-(2-(((1R,2S)-2-aminocyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(((R)-1-cyanoethyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)acetamide(Example 61): To a solution of tert-butyl((1S,2R)-2-((7-(5-(5-((1R,5S,8S)-8-acetamido-3-azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(((R)-1-cyanoethyl)amino)pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)carbamate(synthesized as described in Example P-GJB2 using the appropriateboronate ester in place of I-8) (25.2 mg, 0.035 mmol) in DCM (1.0 mL)was added trifluoroacetic acid (0.5 mL, 7.0 mmol). The reaction mixturewas stirred at RT for 20 minutes, then concentrated in vacuo andpurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productExample 61 as a trifluoroacetate salt.

ES/MS: 627.53 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 9.07 (s, 1H), 8.65 (s, 1H), 8.02 (d,J=5.8 Hz, 1H), 7.97 (s, 1H), 7.70 (d, J=5.1 Hz, 1H), 7.09 (d, J=5.1 Hz,1H), 5.22 (q, J=6.9 Hz, 1H), 4.64 (d, J=4.1 Hz, 1H), 4.07-3.95 (m, 1H),3.81 (d, J=11.9 Hz, 2H), 3.55 (d, J=11.6 Hz, 3H), 2.44 (s, 2H),2.06-1.93 (m, 6H), 1.93-1.72 (m, 8H), 1.75-1.63 (m, 4H), 1.62-1.49 (m,1H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Structure # m/z Procedure Name

62 518.44 2 N-((3R,4S)-1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- hydroxypiperidin-4- yl)acetamide

63 518.43 2 N-((3S,4R)-1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- hydroxypiperidin-4- yl)acetamide

64 518.59 2 N-((3S,4S)-1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- hydroxypiperidin-4- yl)acetamide

65 518.41 2 N-((3R,4R)-1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- hydroxypiperidin-4- yl)acetamide

66 528.57 2 N-(2-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)-2-azabicyclo[2.2.2] octan-4-yl)acetamide

67 528.50 2 7-(5-(5-(7-acetyl-2,7- diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol- 2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2-b] pyridazine-3- carbonitrile

68 500.42 2 7-(5-(5-(6-acetyl-2,6- diazaspiro[3.3]heptan-2-yl)-1,3,4-thiadiazol- 2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

69 542.49 2 N-(2-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4- thiadiazol-2-yl)-2-azaspiro[3.5]nonan-7- yl)acetamide

70 541.30 1 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(oxetan-3- ylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan- 1-yl)acetamide

71 569.43 1 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran- 4-yl)amino)pyridin-3- yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan- 1-yl)acetamide

Procedure 13: Example 72:

(R)-N-(4-(5-(4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)acetamide(Example 72)

(R)-2-((2-chloro-5-iodopyridin-4-yl)amino)propenamide: To a solution of2-chloro-4-fluoro-5-iodo-pyridine (3.50 g, 13.6 mmol) and D-alaninamidehydrochloride (4.23 g, 68.0 mmol) in NMP (30.0 mL) was addedN,N-diisopropylethylamine (11.8 mL, 68.0 mmol). The reaction mixture washeated to 150° C. overnight, then cooled and diluted with water (125mL). The solution was stirred at RT for 2 hours, then the resultingsolid was isolated by vacuum filtration, washed with water, and dried byhigh vacuum. The crude solids were used without additional purification.

ES/MS: 326.24 (M+H⁺)

(R)-2-((5-(5-(4-acetamidobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-2-chloropyridin-4-yl)amino)propenamide:(R)-2-((5-(4-acetamidobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-2-chloropyridin-4-yl)amino)propenamidewas prepared following the protocol in Procedure 1, using theappropriate coupling partners.

ES/MS: 449.28 (M+H⁺)

(R)-N-(4-(5-(6-chloro-4-((1-cyanoethyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)acetamide:(R)-N-(4-(5-(6-chloro-4-((1-cyanoethyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)acetamidewas prepared following the protocol in step 3 of Procedure 11.

ES/MS: 431.33 (M+H⁺)

(R)-N-(4-(5-(4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)acetamide(Example 72): Example 72 was prepared following the protocol in step 4of Procedure 11 using the appropriate coupling partners to provideExample 72 as a trifluoroacetate salt.

ES/MS: 538.39 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.84 (s, 1H), 8.78 (d, J=2.1 Hz, 1H),8.71 (d, J=2.1 Hz, 1H), 8.16 (s, 1H), 8.13 (d, J=5.1 Hz, 1H), 7.25 (d,J=5.1 Hz, 1H), 5.25 (q, J=6.9 Hz, 1H), 2.27-2.16 (m, 6H), 2.17-2.08 (m,6H), 1.92 (d, J=7.0 Hz, 3H), 1.90 (s, 3H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Structure # m/z Procedure Name

73 514.35 2 N-((1R,4R,5R)-2-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-2- azabicyclo[2.2.1]heptan- 5-yl)acetamide

74 514.32 2 N-((1S,4S,5S)-2-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-2- azabicyclo[2.2.1]heptan- 5-yl)acetamide

75 542.35 2 7-(5-(5-(7-acetyl-2,7- diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2- yl)-4-(oxetan-3- ylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

76 570.51 2 7-(5-(5-(7-acetyl-2,7- diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2- yl)-4-((tetrahydro-2H- pyran-4-yl)amino)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

77 553.33 2 (R)-N-(2-(5-(4-((1- cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2- azaspiro[3.5]nonan-7- yl)acetamide

78 556.36 2 N-(2-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(oxetan-3- ylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-2-azaspiro[3.5]nonan-7- yl)acetamide

79 584.36 2 N-(2-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran- 4-yl)amino)pyridin-3- yl)-1,3,4-thiadiazol-2-yl)-2- azaspiro[3.5]nonan-7- yl)acetamide

80 420.26 1 7-(5-(5-(2- hydroxypropan-2-yl)- 1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

81 503.38 1 N-((3R,6S)-6-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran- 3-yl)acetamide

82 515.45 2 7-(5-(5-(7-hydroxy-7- methyl-2- azaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

Procedure 14: Example 83:

N-(1-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetamide(Example 83)

tert-butyl(1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazine-1-carbonyl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate:To a solution of 6-chloro-4-(isopropylamino)nicotinohydrazide (123 mg,0.54 mmol),4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-1-carboxylicacid (175 mg, 0.65 mmol), and HATU (215 mg, 0.57 mmol) in DMF (0.5 mL)was added N,N-diisopropylethylamine (0.31 mL, 1.72 mmol). The reactionmixture was stirred at RT for 15 minutes, then diluted with water (10mL) and extracted with EtOAc (2×10 mL). The combined organic layers weredried over sodium sulfate, isolated by vacuum filtration, concentratedin vacuo, and purified by silica gel column chromatography (eluent:MeOH/DCM) to provide the desired product.

ES/MS: 482.67 (M+H⁺).

tert-butyl(1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate:To a solution of tert-butyl(1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazine-1-carbonyl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate(240 mg, 0.50 mmol) in THF (6.0 mL) at 65° C. was added Lawesson'sReagent (302 mg, 0.75 mmol). The RM was stirred at 65° C. for 15minutes, then concentrated in vacuo and purified by silica gel columnchromatography (eluent: MeOH/DCM) to provide the desired product.

ES/MS: 480.80 (M+H⁺).

N-(1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetamide:Tert-butyl(1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate(152 mg, 0.32 mmol) was suspended in HCl (4M in dioxane, 0.8 mL, 3.17mmol) and heated with stirring at 40° C. for 2 hours. The reactionmixture was cooled and concentrated in vacuo. The resulting residue wassuspended in DCM (2.0 mL). To the suspension was added triethylamine (60μL, 0.43 mmol) and acetic anhydride (11.2 μL, 0.12 mmol). The reactionmixture was stirred at RT for 15 minutes, then concentrated in vacuo andpurified by silica gel column chromatography (eluent: MeOH/DCM) toprovide the desired product.

ES/MS: 422.32 (M+H⁺).

N-(1-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetamide(Example 83): Example 83 was prepared following the protocol in step 4of Procedure 11 using the appropriate coupling partners to provideExample 83 as a trifluoroacetate salt.

ES/MS: 529.36 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J=2.2 Hz, 1H), 8.74 (s, 1H),8.69 (d, J=2.1 Hz, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.95 (s, 1H), 7.23 (d,J=5.0 Hz, 1H), 4.40-4.20 (m, 3H), 2.59-2.24 (m, 6H), 2.15-2.05 (m, 2H),1.91 (s, 3H), 1.48 (d, J=6.4 Hz, 6H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Structure # m/z Procedure Name

83 529.36 14 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4- thiadiazol-2-yl)-2-oxabicyclo[2.2.2] octan-4-yl)acetamide

84 503.32 14 N-((3S,6S)-6-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4- thiadiazol-2-yl)tetrahydro-2H- pyran-3-yl)acetamide

85 572.49 2 N-((1R,5S,8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1]octan- 8-yl)-2-hydroxy-2-methylpropanamide

86 583.37 2 N-((1R,5S,8S)-3-(5-(4- (((R)-1- cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1]octan- 8-yl)-2-hydroxy-2-methylpropanamide

87 586.36 2 N-((1R,5S,8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3- ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)- 3- azabicyclo[3.2.1]octan- 8-yl)-2-hydroxy-2-methylpropanamide

Procedure 15: Example 88:

N-(1-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetamide(Example 88)

2-((1,2-trans)-2-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl)propan-2-ol:To a solution of methyl(1,2-trans)-2-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclobutane-1-carboxylate(prepared following the protocol in steps 1 and 2 of Procedure 14 usingthe appropriate carboxylic acid) (100 mg, 0.24 mmol) in THF (0.5 mL) at0° C. was added methylmagnesium bromide (3M in diethyl ether, 0.12 mL,0.37 mmol). The reaction mixture was allowed to warm to RT with stirringover 30 minutes, then quenched with saturated aqueous ammonium chloride.The reaction was partitioned between water and EtOAc, and the aqueouslayer was extracted two additional times with EtOAc. The combinedorganic layers were dried over sodium sulfate, isolated by vacuumfiltration, concentrated in vacuo, and purified by silica gel columnchromatography (eluent: MeOH/DCM) to provide the desired product.

ES/MS: 411.45, 413.19 (M+H⁺).

7-(5-(5-((1,2-trans)-2-(2-hydroxypropan-2-yl)cyclobutyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 88): Example 88 was prepared following the protocol in step 4of Procedure 11 using the appropriate coupling partners to provideExample 88 as a trifluoroacetate salt and a mixture of trans-stereoisomers.

ES/MS: 474.36 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.71 (d, J=2.2 Hz, 1H), 8.67 (s, 1H),8.64 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=5.0 Hz, 1H), 7.19 (d,J=5.0 Hz, 1H), 4.24 (hept, J=6.1 Hz, 1H), 4.04 (q, J=9.0 Hz, 1H), 2.82(q, J=9.1 Hz, 1H), 2.51-2.32 (m, 1H), 2.30-2.18 (m, 1H), 2.17-2.06 (m,1H), 2.05-1.90 (m, 1H), 1.48 (d, J=6.4 Hz, 6H), 1.17 (s, 3H), 1.13 (s,3H).

The following compound was made according to Proedure 9, using theappropriate starting materials and protecting group chemistry as needed:

ES/MS Structure # m/z Procedure Name

89 486.33 9 7-(5-(5-(4- hydroxybicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)- 4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine- 3-carbonitrile

Procedure 16: Example 90:

(R)-N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-2-hydroxypropanamide(Example 90)

tert-butyl((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate:Tert-butyl((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamatewas prepared from tert-butyl((1R,5S,8s)-3-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(prepared following the protocol in steps 1 and 2 of Procedure 11 usingthe appropriate 2-bromo-thiadiazole in step 1 and the appropriate aminein step 2) following the protocol in step 4 of Procedure 11.

ES/MS: 586.59 (M+H⁺).

7-(5-(5-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride: To a solution of tert-butyl((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(180 mg, 0.31 mmol) in 1,4-dioxane (1.0 mL) was added HCl (4M in1,4-dioxane, 0.77 mL, 3.1 mmol). The reaction mixture was stirred at 40°C. for 1 hour, then concentrated and used without purification.

ES/MS: 486.60 (M+H⁺).

(R)-N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-2-hydroxypropanamide(Example 90): To a solution of7-(5-(5-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (12.0 mg, 0.023 mmol) and (R)-2-hydroxypropanoic acid (2.7mg, 0.03 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine (20.5μL, 0.12 mmol). To the solution was added HATU (13.1 mg, 0.035 mmol) inDMF (0.5 mL). The reaction mixture was stirred at RT for 15 minutes thenpurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productExample 90 as a trifluoroacetate salt.

ES/MS: 558.42 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.2Hz, 1H), 8.48 (s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.87 (s, 1H), 7.50 (d,J=6.1 Hz, 1H), 7.23 (d, J=5.1 Hz, 1H), 4.29 (p, J=6.4 Hz, 1H), 4.14 (q,J=6.8 Hz, 1H), 4.01 (d, J=6.0 Hz, 1H), 3.82 (dd, J=12.1, 3.1 Hz, 2H),3.56 (d, J=11.9 Hz, 2H), 2.49 (s, 2H), 2.02-1.96 (m, 2H), 1.81-1.65 (m,2H), 1.47 d, J=6.4 Hz, 6H), 1.36 (d, J=6.8 Hz, 3H).

The following compounds were made according to Procedure 16, using theappropriate starting materials and protecting group chemistry as needed:

ES/MS Pro- Structure # m/z cedure Name

91 558.40 16 (S)-N-((1R,5S,8s)- 3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin- 7-yl)-4- (isopropylamino) pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-3-azabicyclo [3.2.1]octan-8- yl)-2-hydroxy propanamide

92 598.48 16 (1r,3R)-N-((1R,5S, 8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isropropylamino) pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-3-azabicyclo [3.2.1]octan-8-yl)-3- hydroxy-3-methyl- cyclobutane-1-carboxamide

93 598.49 16 (1s,3S)-N-((1R,5S, 8s)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)- 4-(isopropylamino) pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-3-azabicyclo [3.2.1]octan-8-yl)-3- hydroxy-3-methyl- cyclobutane-1-carboxamide

94 584.56 16 N-((1R,5S,8s)-3- (5-(6-(3- cyanopyrrolo [1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-3-azabicyclo [3.2.1]octan-8-yl)- 3-methyloxetane- 3-carboxamide

95 612.43 16 N-((1R,5S,8s)-3- (5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)- 4-(isopropylamino) pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-3-azabicyclo [3.2.1]octan-8-yl)- 4-methyltetrahydro- 2H-pyran-4-carboxamide

Procedure 17: Example 96:

N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-4-methylpiperazine-1-carboxamide(Example 96)

N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-4-methylpiperazine-1-carboxamide(Example 96): To a suspension of7-(5-(5-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (synthesized following the protocol in Procedure 16) (12.0mg, 0.023 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine(20.5 μL, 0.12 mmol). To the resulting solution was added a solution of4-methylpiperazine-1-carbonyl chloride hydrochloride (6.0 mg, 0.030mmol) and N,N-diisopropylethylamine (8.2 μL, 0.046 mmol) in DMF (0.5mL). The reaction mixture was stirred at RT for 3 hours then directlypurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productExample 96 as a trifluoroacetate salt.

ES/MS: 612.35 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.2 Hz, 1H), 8.68 (d, J=2.1Hz, 1H), 8.49 (s, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.87 (s, 1H), 7.23 (d,J=5.1 Hz, 1H), 4.38-4.10 (m, 3H), 3.88 (s, 1H), 3.80 (dd, J=12.2, 3.1Hz, 2H), 3.62-3.44 (m, 4H), 3.25-3.02 (m, 4H), 2.94 (s, 3H), 2.50 (s,2H), 2.11-1.96 (m, 2H), 1.73-1.61 (m, 2H), 1.47 (d, J=6.4 Hz, 6H).Additional peak obscured by solvent.

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z cedure Name

 97 600.34 16 3-(((1R,5S,8s)-3-(5- (6-(3-cyanopyrrolo[1,2-b]pyridazin-7- yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2- yl)-3-azabicyclo [3.2.1]octan-8-yl) amino)-2,2-dimethyl-3-oxopropanoic acid

 98 619.38 16 N-((1R,5S,8s)-3- (5-(6-(3-cyano- pyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1] octan-8-yl)-2- ((dimethyl(oxo)-l6-sulfanylidene)amino) acetamide

 99 570.36  2 N-(2-(5-(6-(3- cyanopyrrolo [1,2-b]pyridazin- 7-yl)-4-((3-methyloxetan-3- yl)amino)pyridin- 3-yl)-1,3,4- thiadiazol-2-yl)-2-azaspiro[3.5]nonan- 7-yl)acetamide

100 611.41 16 N-((1R,5S,8s)- 3-(5-(6-(3- cyanopyrrolo [1,2-b]pyridazin-7-yl)-4-(isopropyl- amino)pyridin- 3-yl)-1,3-thiadiazol-2-yl)-3-azabicyclo [3.2.1]octan-8-yl)-1- methylpiperidine-4- carboxamide

101 614.40  2 N-((1R,5S,8s)-3- (5-(6-(3-cyanopyrrolo [1,2-b]pyridazin-7-yl)-4-((tetrahydro- 2H-pyran-4-yl)amino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1] octan-8-yl)-2- hydroxy-2-methylpropanamide

102 584.4 16 N-((1R,5S,8s)-3- (5-(6-(3-cyano- pyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)-3-azabicyclo [3.2.1]octan-8-yl)-1- methylazetidine-3- carboxamide

103 633.39 16 N1-((1R,5S,8s)-3- (5-(6-(3-cyano- pyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)-3-azabicyclo [3.2.1]octan-8-yl)- N2-(dimethyl(oxo)-l6-sulfanylidene) oxalamide

Procedure 18: Example 104:

4-acetyl-N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperazine-1-carboxamide(Example 104)

N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperazine-1-carboxamidehydrochloride: Tert-butyl4-(((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamoyl)piperazine-1-carboxylate(synthesized following the protocol in Procedure 2 using the appropriatecoupling partners) (130 mg, 0.19 mmol) was stirred in a solution of HCl(4M in 1,4-dioxane, 0.93 mL, 3.73 mmol) at 40° C. for 1 hour. Thereaction mixture was concentrated and the resulting solid used withoutpurification.

ES/MS: 598.42 (M+H⁺)

4-acetyl-N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperazine-1-carboxamide(Example 104): To a suspension of crudeN-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperazine-1-carboxamidehydrochloride (10.0 mg, 0.016 mmol) in DMF was added triethylamine (8.8μL, 0.063 mmol) followed by acetic anhydride (1.8 μL, 0.019 mmol). Thereaction mixture was stirred at RT for 15 minutes, then directlypurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productExample 104 as a trifluoroacetate salt.

ES/MS: 640.41 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.2 Hz, 1H), 8.68 (d, J=2.2Hz, 1H), 8.48 (s, 1H), 8.06 (d, J=5.0 Hz, 1H), 7.87 (s, 1H), 7.23 (d,J=5.0 Hz, 1H), 4.29 (p, J=6.4 Hz, 1H), 3.88 (s, 1H), 3.80 (dd, J=12.3,3.1 Hz, 2H), 3.66-3.52 (m, 6H), 3.51-3.47 (m, 2H), 3.45-3.39 (m, 2H),2.50 (s, 2H), 2.13 (s, 3H), 2.08-2.00 (m, 2H), 1.72-1.59 (m, 2H), 1.47(d, J=6.4 Hz, 6H).

The following compounds were made according to Procedure 18, using theappropriate starting materials and protecting group chemistry as needed:

ES/MS Pro- Structure # m/z cedure Name

105 656.45 18 methyl 4- (((1R,5S, 8s)-3- (5-(6-(3- cyanopyrrolo [1,2-b]pyridazin-7- yl)-4- (isopropyl- amino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)-3-aza- bicyclo[3.2.1] octan-8-yl) carbamoyl)piperazine- 1-carboxylate

106 676.36 18 N-((1R, 5S,8s)- 3-(5-(6-(3- cyanopyrrolo [1,2-b]pyridazin-7- yl)-4- (isopropyl- amino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)-3- azabicyclo [3.2.1]octan- 8-yl)-4- (methyl-sulfonyl) piperazine- 1-carboxamide

Procedure 19: Example 107:

7-(5-(5-(6-(2-((dimethyl(oxo)-16-sulfanylidene)amino)acetyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 107)

7-(5-(5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile:A solution of tert-butyl3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate(synthesized following the protocol in Procedure 2 using the appropriatecoupling partners) (153 mg, 0.28 mmol) in1,1,1,3,3,3-hexafluoro-2-propanol (1.9 mL, 17.9 mmol) was heated in amicrowave reactor 30 minutes at 150° C. The cooled reaction wasconcentrated in vacuo to provide the desired product which was usedwithout purification.

ES/MS: 458.45 (M+H⁺)

7-(5-(5-(6-(2-((dimethyl(oxo)-λ⁶-sulfanylidene)amino)acetyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 107): To a solution of crude7-(5-(5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(15.0 mg, 0.033 mmol) and2-((dimethyl(oxo)-λ⁶-sulfanylidene)amino)acetic acid (6.4 mg, 0.043mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine (23 μL, 0.13mmol) followed by the addition of a solution of HATU (18.7 mg, 0.049mmol) in DMF (0.5 mL). The reaction mixture was stirred at RT for 15minutes then directly purified by RP-HPLC (eluent: water/MeCN*0.1% TFA)to yield the product Example 107 as a trifluoroacetate salt.

ES/MS: 591.31 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J=2.2 Hz, 1H), 8.68 (d, J=2.2Hz, 1H), 8.53 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.88 (s, 1H), 7.23 (d,J=5.0 Hz, 1H), 4.65 (s, 1H), 4.30 (p, J=6.2 Hz, 1H), 4.17 (dd, J=32.3,11.3 Hz, 2H), 3.96-3.76 (m, 4H), 3.30 (s, 6H), 3.02 (s, 1H), 2.98-2.91(m, 1H), 1.85 (d, J=9.3 Hz, 1H), 1.48 (d, J=6.4 Hz, 6H).

Procedure 20: Example 108:

7-(4-(isopropylamino)-5-(5-(6-(4-methylpiperazine-1-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 108)

7-(4-(isopropylamino)-5-(5-(6-(4-methylpiperazine-1-carbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 108): To a solution of crude7-(5-(5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(synthesized as described in Procedure 19) (15 mg, 0.033 mmol) in DMF(0.5 mL) was added N,N-diisopropylethylamine (11.7 μL, 0.066 mmol) asolution of 4-methylpiperazine-1-carbonyl chloride hydrochloride (8.5mg, 0.43 mmol) and N,N-diisopropylethylamine (11.7 μL, 0.066 mmol) inDMF (0.5 mL). The reaction mixture was stirred at RT for 3 hours thendirectly purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield theproduct Example 108 as a trifluoroacetate salt.

ES/MS: 584.46 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.2Hz, 1H), 8.54 (s, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 7.23 (d,J=5.0 Hz, 1H), 4.49 (d, J=6.4 Hz, 2H), 4.35-4.19 (m, 3H), 4.20-3.0 (brm, 8H), 3.73 (d, J=11.3 Hz, 2H), 2.97-2.81 (m, 4H), 1.75 (d, J=9.2 Hz,1H), 1.47 (d, J=6.4 Hz, 6H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z cedure Name

109 647.35 19 N-((1R,5S,8s)-3- (5-(6-(3-cyano- pyrrolo[1,2-b]pyridazin-7- yl)-4-((3- methyloxetan-3- yl)amino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)- 3-azabicyclo [3.2.1]octan-8- yl)-2-((dimethyl(oxo)-l6- sulfanylidene) amino) acetamide

110 640.36 20 N-((1R,5S,8s)- 3-(5-(6-(3- cyanopyrrolo [1,2-b]pyridazin-7-yl)-4-((3- methyloxetan- 3-yl)amino) pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-3- azabicyclo [3.2.1]octan-8- yl)-4-methyl- piperazine-1-carboxamide

111 528.32 20 7-(5-(5-(6- acetyl-3,6- diazabicyclo [3.1.1]heptan-3-yl)-1,3,4- thiadiazol-2- yl)-4-((3- methyloxetan- 3-yl)amino)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

112 572.39 19 7-(5-(5-(6-(2- hydroxy-2-methyl- propanoyl)-3,6-diazabicyclo [3.1.1]heptan- 3-yl)-1,3,4- thiadiazol-2- yl)-4-((3-methyloxetan-3- yl)amino)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3-carbonitrile

113 619.30 19 7-(5-(5-(6-(2- ((dimethyl(oxo)- l6-sulfanylidene) amino)acetyl)-3,6- diazabicyclo [3.1.1]heptan- 3-yl)-1,3,4- thiadiazol-2-yl)-4-((3-methyl- oxetan-3-yl) amino)pyridin-2- yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

114 612.34 20 7-(4-((3-methyl- oxetan-3-yl) amino)-5-(5-(6- (4-methyl-piperazine-1- carbonyl)-3,6- diazabicyclo [3.1.1]heptan-3- yl)-1,3,4-thiadiazol-2- yl)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

115 555.30  2 7-(4-(((R)-1- cyanoethyl)amino)- 5-(5-(6-(2- hydroxy-2-methylpropanoyl)- 3,6-diazabicyclo [3.1.1]heptan- 3-yl)-1,3,4-thiadiazol-2- yl)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

Procedure 21: Example 116:

N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-4-(oxetan-3-yl)piperazine-1-carboxamide(Example 116)

N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-4-(oxetan-3-yl)piperazine-1-carboxamide(Example 116): To a suspension of crudeN-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperazine-1-carboxamidehydrochloride (20.0 mg, 0.032 mmol) in DMF (1.0 mL) was added3-oxetanone (9.1 mg, 0.13 mmol), sodium triacetoxyborohydride (33.4 mg,0.16 mmol), and acetic acid (9.0 μL, 0.16 mmol). The reaction mixturewas stirred at RT for 90 minutes then directly purified by RP-HPLC(eluent: water/MeCN*0.1% TFA) to yield the product Example 116 as atrifluoroacetate salt.

ES/MS: 654.43 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.2Hz, 1H), 8.49 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.87 (s, 1H), 7.23 (d,J=5.0 Hz, 1H), 4.92-4.83 (m, 2H), 4.82-4.76 (m, 2H), 4.38-4.25 (m, 2H),3.88 (s, 1H), 3.80 (dd, J=12.3, 3.1 Hz, 2H), 3.71 (s, 4H), 3.60-3.51 (m,2H), 3.18-3.08 (m, 4H), 2.49 (s, 2H), 2.08-1.95 (m, 2H), 1.72-1.62 (m,2H), 1.47 (d, J=6.4 Hz, 6H).

The following compounds were made according to Procedure 19, using theappropriate starting materials and protecting group chemistry as needed:

ES/MS Pro- Structure # m/z cedure Name

117 583.42 19 7-(4-(isopropyl- amino)-5-(5-(6-(1- methylpiperidine-4-carbonyl)-3,6- diazabicyclo [3.1.1]heptan- 3-yl)-1,3,4-thiadiazol-2-yl) pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

118 611.35 19 7-(4-((3-methyl- oxetan-3-yl) amino)-5-(5-(6- (1-methyl-piperidine-4- carbonyl)-3,6- diazaspiro[3.1.1] heptan-3-yl)- 1,3,4-thiadiazol-2-yl) pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

119 639.37 19 N-((1R,5S,8s)-3- (5-(6-(3- cyanopyrrolo [1,2-b]pyridazin-7-yl)-4-((3- methyloxetan-3- yl)amino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)- 3-azabicyclo [3.2.1]octan- 8-yl)-1-methyl-piperidine-4- carboxamide

Procedure 22: Example 120:

N-(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)-2-hydroxy-2-methylpropanamide(Example 120)

tert-butyl(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate:Tert-butyl(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamatewas synthesized from tert-butyl(4-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate(synthesized following the protocol in steps 1 and 2 of Procedure 14using the appropriate carboxylic acid) following the protocol in step 4of Procedure 14.

ES/MS: 585.62 (M+H⁺)

7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile:A solution of tert-butyl(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamatein 1,1,1,3,3,3-hexafluoro-2-propanol was heated at 150° C. in amicrowave reactor for 90 minutes. The cooled reaction mixture wasconcentrated to provide the desired product which was used withoutpurification.

ES/MS: 485.47 (M+H⁺)

N-(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)-2-hydroxy-2-methylpropanamide(Example 120): To a solution of crude7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(10.0 mg, 0.021 mmol) and 2-hydroxy-2-methylpropanoic acid (2.8 mg,0.027 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine (14.7μL, 0.083 mmol) followed by a solution of HATU (11.8 mg, 0.031 mmol) inDMF (0.5 mL). The reaction mixture was stirred at RT for 15 minutes thendirectly purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield theproduct Example 120 as a trifluoroacetate salt.

ES/MS: 571.49 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J=2.2 Hz, 1H), 8.71 (s, 1H),8.69 (d, J=2.1 Hz, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.95 (s, 1H), 7.24 (d,J=5.1 Hz, 1H), 4.31 (p, J=6.3 Hz, 1H), 2.27-2.09 (m, 12H), 1.49 (d,J=6.4 Hz, 6H), 1.34 (s, 6H).

The following compounds were made according to Procedure 22, using theappropriate starting materials and protecting group chemistry as needed:

ES/MS Pro- Structure # m/z cedure Name

121 618.34 22 N-(4-(5-(6-(3-cyano- pyrrolo[1,2-b] pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)bicyclo[2.2.2]octan- 1-yl)-2-((dimethyl (oxo)-l6- sulfanylidene)amino)acetamide

122 610.43 22 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)bicyclo[2.2.2]octan- 1-yl)-1- methylpiperidine-4- carboxamide

Procedure 23: Example 123:

1-acetyl-N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperidine-4-carboxamide(Example 123)

7-(5-(5-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride: Tert-butyl((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate(synthesized following the protocol in Procedure 2 using the appropriatecoupling partners) (451 mg, 0.77 mmol) was stirred with HCl (4M in1,4-dioxane, 3.9 mL, 15.4 mmol) at 40° C. for 1 hour. The cooledreaction was concentrated in vacuo to provide the desired product whichwas used without purification.

ES/MS: 486.38 (M+H⁺)

tert-butyl4-(((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamoyl)piperidine-1-carboxylate:To a solution of crude7-(5-(5-((1R,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (50.0 mg, 0.096 mmol) and1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (65.9 mg, 0.29 mmol)in DMF (0.5 mL) was added N,N-diisopropylamine (0.21 mL) followed by asolution of HATU (142 mg, 0.37 mmol) in DMF (0.5 mL). The reactionmixture was stirred at RT for 15 minutes then partitioned between waterand EtOAc. The aqueous layer was extracted with two additional portionsof EtOAc. The combined organic layers were dried over sodium sulfate,isolated by vacuum filtration, and purified by silica gel columnchromatography (eluent: EtOAc/hexanes) to provide the desired product.

ES/MS: 697.54 (M+H⁺).

N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperidine-4-carboxamide:A solution of tert-butyl4-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamoyl)piperidine-1-carboxylate(135 mg, 0.19 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (2.0 mL, 19.4mmol) was heated in a microwave reactor for 75 minutes at 140° C. Thecooled reaction was concentrated to provide the desire product which wasused without purification.

ES/MS: 697.39 (M+H⁺).

1-acetyl-N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperidine-4-carboxamide(Example 123): To a solution of crudeN-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperidine-4-carboxamide(10.0 mg, 0.017 mmol) in DMF (1.0 mL) was added triethylamine (7.0 μL,0.050 mmol) followed by acetic anhydride (2.0 μL, 0.022 mmol). Thereaction mixture was stirred at RT for 15 minutes then directly purifiedby RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product Example123 as a trifluoroacetate salt.

ES/MS: 639.46 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.2Hz, 1H), 8.48 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.90 (d, J=5.6 Hz, 1H),7.87 (s, 1H), 7.23 (d, J=5.1 Hz, 1H), 4.54 (d, J=13.3 Hz, 1H), 4.29 (p,J=6.4 Hz, 1H), 4.09-3.92 (m, 2H), 3.86-3.75 (m, 2H), 3.54 (d, J=12.0 Hz,2H), 3.23-3.10 (m, 1H), 2.68 (td, J=12.9, 2.9 Hz, 1H), 2.53 (tt, J=11.4,3.9 Hz, 1H), 2.44 (s, 2H), 2.11 (s, 3H), 2.06-1.97 (m, 2H), 1.88-1.74(m, 2H), 1.74-1.63 (m, 3H), 1.58 (qd, J=12.6, 4.4 Hz, 1H), 1.47 (d,J=6.4 Hz, 6H).

Procedure 24: Example 124:

N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide(Example 124)

N-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide(Example 124): To a solution of crudeN-((1R,5S,8s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)piperidine-4-carboxamide(10.0 mg, 0.017 mmol) and 3-oxetanone (4.8 mg, 0.067 mmol) in DMF (1.0mL) was added acetic acid (4.8 μL, 0.084 mmol) and sodiumtriacetoxyborohydride (17.8 mg, 0.084 mmol). The reaction mixture wasstirred at 40° C. for 30 minutes, then directly purified by RP-HPLC(eluent: water/MeCN*0.1% TFA) to yield the product Example 124 as atrifluoroacetate salt.

ES/MS: 653.42 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.2Hz, 1H), 8.49 (s, 1H), 8.07 (d, J=5.1 Hz, 1H), 8.03 (d, J=5.5 Hz, 1H),7.87 (s, 1H), 7.23 (d, J=5.0 Hz, 1H), 4.79 (dd, J=8.3, 5.7 Hz, 2H), 4.39(s, 1H), 4.29 (p, J=6.5 Hz, 1H), 3.99 (d, J=5.4 Hz, 1H), 3.81 (dd,J=12.4, 3.1 Hz, 2H), 3.62-3.51 (m, 3H), 2.95-2.81 (m, 2H), 2.68-2.53 (m,1H), 2.45 (s, 2H), 2.19-1.91 (m, 7H), 1.77-1.64 (m, 2H), 1.47 (d, J=6.4Hz, 6H). Additional peak obscured by solvent.

The following compounds were made according to Procedure 1, using theappropriate starting materials and protecting group chemistry as needed:

ES/MS Structure # m/z Procedure Name

125 527.457 1 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)cyclo- propanecarboxamide

126 517.607 1 methyl ((1r,4r)-4-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate

127 501.585 1 N-((1s,4s)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide

128 487.538 1 7-(5-(5-(1- acetylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

Procedure 25: Example 129:

7-(4-(isopropylamino)-5-(5-(piperidin-4-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 129)

7-(4-(isopropylamino)-5-(5-(piperidin-4-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 129): To an RBF with tert-butyl4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate(prepared via Procedure 1) (40 mg, 0.061 mmol) was added 1,4-dioxane (7mL) and methanol (1.5 mL). HCl (4.0M in dioxane, 1 mL) was added, andthe reaction was stirred at 50° C. for 2 hours. The reaction was thenconcentrated under reduced pressure, and the crude material wasdissolved in DMF, then purified by RP-HPLC (eluent: water/MeCN*0.1% TFA)to yield the product Example 129 as a trifluoroacetate salt.

ES/MS: 445.530 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J=2.2 Hz, 1H), 8.77 (s, 1H),8.71 (d, J=2.2 Hz, 1H), 8.11 (d, J=5.0 Hz, 1H), 8.01 (s, 1H), 7.26 (d,J=5.0 Hz, 1H), 4.41-4.25 (m, 1H), 3.84-3.65 (m, 1H), 3.65-3.50 (m, 2H),3.26 (d, J=12.6 Hz, 2H), 2.50 (d, J=14.2 Hz, 2H), 2.29-2.12 (m, 2H),1.51 (d, J=6.4 Hz, 6H).

The following compounds were made according to Procedure 2, using theappropriate starting materials and protecting group chemistry as needed:

ES/MS Structure # m/z Procedure Name

130 446.531 2 7-(4-(isopropylamino)-5- (5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3-carbonitrile

131 447.380 2 7-(4-(isopropylamino)-5- (5-morpholino-1,3,4-thiadiazol-2-yl)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3-carbonitrile

Procedure 26: Example 132:

±7-(5-(5-(trans-2-(2-hydroxypropan-2-yl)cyclopropyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 132)

±methyltrans-2-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclopropane-1-carboxylate:To a vial was added7-(5-bromo-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-2) (60 mg, 0.168 mmol), (±) methyltrans-2-(1,3,4-thiadiazol-2-yl)cyclopropane-1-carboxylate (I-20) (47 mg,0.253 mmol), Pd(OAc)₂ (9.5 mg, 0.042 mmol), Xantphos (49 mg, 0.084mmol), copper(I) iodide (16 mg, 0.084 mmol), and cesium carbonate (165mg, 0.5 mmol). 1,4-Dioxane (1 mL), was added, and the mixture wasdegassed with argon for 1 minute. The vial was sealed and stirred 2hours at 105° C. Afterward, the vial was cooled and the crude materialwas diluted with DMF (0.5 mL). This mixture was filtered, and purifiedby RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product as atrifluoroacetate salt. The purified material was dissolved in EtOAc andneutralized with sat. aq. NaHCO₃. The layers were separated, and theorganic layer was dried over MgSO4, filtered, and concentrated underreduced pressure.

ES/MS: 460.550 (M+H⁺)

±7-(5-(5-(trans-2-(2-hydroxypropan-2-yl)cyclopropyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 132): To a solution of ±methyltrans-2-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclopropane-1-carboxylate(40 mg, 0.087 mmol) in THF (2 mL) at −78° C. was added methyllithium(1.6M in ether, 0.16 mL, 0.26 mmol) dropwise. The reaction was quenchedat −78° C. with dropwise addition of saturated aqueous ammoniumchloride, then slowly allowed to warm to room temperature. The reactionwas partitioned between water and EtOAc, and the aqueous layer wasextracted two additional times with EtOAc. The combined organic layerswere dried over magnesium sulfate, filtered, concentrated under reducedpressure, and then purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) toyield the product Example 132 as a trifluoroacetate salt.

ES/MS: 460.413 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J=2.2 Hz, 1H), 8.71 (d, J=2.2Hz, 1H), 8.68 (s, 1H), 8.09 (d, J=5.1 Hz, 1H), 7.96 (s, 1H), 7.26 (d,J=5.1 Hz, 1H), 4.40-4.23 (m, 1H), 2.63 (dt, J=9.1, 4.8 Hz, 1H), 1.81(ddd, J=9.3, 6.7, 4.6 Hz, 1H), 1.56-1.43 (m, 7H), 1.43-1.28 (m, 7H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z cedure Name

132 Isomer 1 460.487 26 7-(5-(5-((1R,2R)-2-(2- hydroxypropan-2-yl)cyclopropyl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3-carbonitrile

132 Isomer 2 460.586 26 7-(5-(5-((1S,2S)-2-(2- hydroxypropan-2-yl)cyclopropyl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3-carboxamide

133 509.466  1 7-(5-(5-(1-(2,2- difluoroethyl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin-2- yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile

134 626.725  1 methyl (((1R,3r)-3-((2-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-5-(5- ((1r,4R)-4- (cyclopropanecarboxamido)cyclohexyl)-1,3,4- thiadiazol-2-yl)pyridin-4- yl)amino)cyclobutyl)methyl)carbamate

135 541.582  1 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)cyclo- propanecarboxamide

Procedure 30: Example 136:

7-(5-(5-(trans-2-(2-hydroxypropan-2-yl)cyclopropyl)-1,3,4-thiadiazol-2-yl)-4-(oxetan-3-ylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile('Example 136):

methyltrans-2-(5-(6-chloro-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclopropane-1-carboxylate:To a vial was added 2-chloro-5-iodo-N-(oxetan-3-yl)pyridin-4-amine(synthesized in step 1 of I-34) (60 mg, 0.0.19 mmol), (±) methyltrans-2-(1,3,4-thiadiazol-2-yl)cyclopropane-1-carboxylate (1-20) (40 mg,0.213 mmol), Pd(OAc)₂ (8.7 mg, 0.039 mmol), Xantphos (45 mg, 0.077mmol), copper(I) iodide (15 mg, 0.077 mmol), and cesium carbonate (189mg, 0.58 mmol). 1,4-Dioxane (1 mL), was added, and the mixture wasdegassed with argon for 1 minute. The vial was sealed and stirred 90minutes at 105° C. Afterward, the vial was cooled and the crude materialwas diluted with DMF (0.5 mL). This mixture was filtered, and purifiedby RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product as atrifluoroacetate salt. The purified material was dissolved in EtOAc andneutralized with sat. aq. NaHCO₃. The layers were separated, and theorganic layer was dried over MgSO₄, filtered, and concentrated underreduced pressure.

ES/MS: 367.290 (M+H⁺)

2-(trans-2-(5-(6-chloro-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclopropyl)propan-2-ol:To a solution of methyltrans-2-(5-(6-chloro-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclopropane-1-carboxylate(80 mg, 0.218 mmol) in THF (10 mL) at −78° C. was added methyllithium(1.6M in ether, 0.2 mL, 0.33 mmol) dropwise, and the reaction wasstirred 5 minutes at −78° C. The reaction was quenched at −78° C. withdropwise addition of 1 mL saturated aqueous ammonium chloride, thenslowly allowed to warm to room temperature. The reaction was partitionedbetween water and EtOAc, and the aqueous layer was extracted twoadditional times with EtOAc. The combined organic layers were dried overmagnesium sulfate, filtered, concentrated under reduced pressure, andthen purified by silica gel chromatography (eluent: EtOAc/hexanes, thenMeOH/EtOAc) to yield the product.

ES/MS: 367.195 (M+H⁺)

7-(5-(5-(trans-2-(2-hydroxypropan-2-yl)cyclopropyl)-1,3,4-thiadiazol-2-yl)-4-(oxetan-3-ylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(±P-SEA6): A microwave vial was charged with2-(trans-2-(5-(6-chloro-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclopropyl)propan-2-ol(50 mg, 0.136 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-8, 51.3 mg, 0.191 mmol), and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.027 mmol). To the flask was added1,4-dioxane (1.0 mL) and a 2M aqueous solution of sodium carbonate(0.136 mL, 0.27 mmol). The reaction mixture was degassed by bubblingargon for 30 seconds. The vial was sealed and heated with stirring at120° C. for 20 minutes in a microwave reactor. The cooled reactionmixture was concentrated and purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product -Example 136 as a trifluoroacetate salt.

ES/MS: 474.503 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J=2.2 Hz, 1H), 8.77-8.72 (m,2H), 8.08 (d, J=5.1 Hz, 1H), 7.73 (s, 1H), 7.25 (d, J=5.1 Hz, 1H),5.37-5.13 (m, 3H), 4.82 (dd, J=6.7, 5.3 Hz, 2H), 2.65 (dt, J=8.7, 4.9Hz, 1H), 1.82 (ddd, J=9.3, 6.7, 4.6 Hz, 1H), 1.54 (ddd, J=8.8, 6.8, 4.7Hz, 1H), 1.46-1.24 (m, 7H).

Single isomers were isolated by chiral supercritical fluidchromatography separation.

The following compounds were made according to the previous pocedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z cedure Name

136 Isomer 1 474.358 7-(5-(5-((1S,2S)-2- (2-hydroxypropan-2-yl)cyclopropyl)- 1,3,4-thiadiazol-2- yl)-4-(oxetan-3- ylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

136 Isomer 2 474.324 7-(5-(5-((1R,2R)-2- (2-hydroxypropan-2-yl)cyclopropyl)- 1,3,4-thiadiazol-2- yl)-4-(oxetan-3- ylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

136 Isomer 3 474.366 7-(5-(5-((1S,2R)-2- (2-hydroxypropan-2-yl)cyclopropyl)- 1,3,4-thiadiazol-2- yl)-4-(oxetan-3- ylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

136 Isomer 4 474.366 7-(5-(5-((1R,2S)-2- (2-hydroxypropan-2-yl)cyclopropyl)- 1,3,4-thiadiazol-2- yl)-4-(oxetan-3- ylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

137 514.642 2 N-((1R,4R,7R)-2-(5- (6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2- azabicyclo[2.2.1] heptan-7-yl) acetamide

138 501.588 1 7-(4- (isopropylamino)-5- (5-(1-(oxetan-3-yl)piperidin-4-yl)- 1,3,4-thiadiazol-2- yl)pyridin-2- yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

139 572.739 1 N-((1r,4r)-4-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)cyclohexyl) morpholine-4- carboxamide

140 516.411 1 1-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)cyclohexyl)-3- methylurea

141 514.422 2 N-((1R,2R,4S)-7-(5- (6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-7- azabicyclo[2.2.1] heptan-2-yl) acetamide

142 586.500 1 N-((1r,4r)-4-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3- ylamino)pyridin-3- yl)-1,3,4-thiadiazol-2- yl)cyclohexyl) morpholine-4- carboxamide

143 671.672 1 methyl (((1R,3r)-3- ((2-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-5- (5-((1r,4R)-4- (morpholine-4- carboxamido)cyclohexyl)-1,3,4- thiadiazol-2- yl)pyridin-4- yl)amino)cyclobutyl)methyl)carbamate

144 556.350 2 N-((1R,5S,8s)-3-(5- (6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- ((3-methyloxetan-3- yl)amino)pyridin-3-yl)-1,3,4-thiadiazol- 2-yl)-3- azabicyclo[3.2.1] octan-8-yl)acetamide

145 501.322 2 7-(5-(5-((1R,5S)-8- oxa-3- azabicyclo[3.2.1]octan-3-yl)-1,3,4- thiadiazol-2-yl)-4- ((3-methyloxetan-3-yl)amino)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

146 487.353 2 7-(5-(5-((1R,5S,8r)- 8-hydroxy-3- azabicyclo[3.2.1]octan-3-yl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo [1,2-b]pyridazine-3- carbonitrile

147 566.469 2 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((3-methyloxetan-3- yl)amino)pyridin-3- yl)-1,3,4-thiadiazol- 2-yl)-3,3-difluoropiperidin-4- yl)acetamide

147 Isomer 1 566.499 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- ((3-methyloxetan-3- yl)amino)pyridin-3-yl)-1,3,4-thiadiazol- 2-yl)-3,3- difluoropiperidin-4- yl)acetamide

147 Isomer 2 566.321 (S)-N-(1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- ((3-methyloxetan-3- yl)amino)pyridin-3-yl)-1,3,4-thiadiazol- 2-yl)-3,3- difluoropiperidin-4- yl)acetamide

Procedure 27: Example 148:

N-((1R,5S,8S)-3-(5-(4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)cyclopropanecarboxamide(Example 148)

N-((1R,5S,8S)-3-(5-(4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)cyclopropanecarboxamide(Example 148): To a vial containing(R)-(4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)boronicacid as a trifluoroacetate salt (25 mg, 0.056 mmol),N-((1R,5S,8s)-3-(5-bromo-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl)cyclopropanecarboxamide(20 mg, 0.056 mmol), Pd(dppf)Cl₂ (1.8 mg, 0.014 mmol), was added1,4-dioxane (1 mL) and sodium carbonate (2M Aqueous, 0.085 mL, 0.17mmol). The mixture was degassed with argon for 30 seconds, sealed, andheated for 1 hour at 120° C. Afterward, the vial was cooled and thecrude material was diluted with DMF (0.5 mL). This mixture was filtered,and purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield theproduct Example 148 as a trifluoroacetate salt.

ES/MS: 565.573 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J=2.2 Hz, 1H), 8.71 (d, J=2.2Hz, 1H), 8.64 (s, 1H), 8.16-8.08 (m, 2H), 7.27 (d, J=5.1 Hz, 1H), 5.24(q, J=7.0 Hz, 1H), 4.02 (s, 1H), 3.84 (d, J=12.1 Hz, 2H), 3.57 (d,J=11.9 Hz, 2H), 2.47 (s, 2H), 2.13-2.03 (m, 2H), 1.92 (d, J=6.9 Hz, 3H),1.77-1.60 (m, 3H), 0.88 (dt, J=6.1, 3.1 Hz, 2H), 0.79 (dt, J=8.1, 3.2Hz, 2H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Structure # m/z Procedure Name

149 515.332 2 7-(5-(5-((1R,5R,8r)-8- hydroxy-3- azabicycl[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2- yl)-4-((3-methyloxetan- 3-yl)amino)pyridin-2-yl)pyrroloo[1,2-b] pyridazine-3-carbonitrile

150 554.440 2 N-((1R,5S,8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1]octan- 8- yl)cyclopropanecarbomide

151 549.286 27 N-((R)-1-(5-(4-(((R)-1- cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,3- difluoropiperidin-4- yl)acetamide

152 549.292 27 N-((S)-1-(5-(4-(((R)-1- cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3,3- difluoropiperidin-4- yl)acetamide

153 501.420 2 7-(5-(5-((1R,5S,8r)-8- hydroxy-8-methyl-3-azabicyclo[3.2.1]octan- 3-yl)-1,3,4-thiadiazol-2- yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

154 487.381 2 7-(5-(5-((1R,5S,8s)-8- hydroxy-3- azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

155 542.465 2 N-((1R,5S,8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-8-methyl-3- azabicyclo[3.2.1]octan- 8-yl)acetamide

156 569.655 1 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- ((tetrahydro-2H-pyran- 4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl) cyclopropanecarboxamide

157 553.480 27 N-((1R,5S,8S)-3-(5-(4- (((R)-1- cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-8- methyl-3- azabicyclo[3.2.1]octan- 8-yl)acetamide

158 555.630 1 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((3- methyloxetan-3- yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)cyclopro- panecarboxamide

159 555.574 2 7-(5-(5-(8-hydroxy-8- (trifluoromethyl)-3-azabicyclo[3.2.1]octan- 3-yl)-1,3,4-thiadiazol-2- yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

160 538.404 13 N-((1R,4r)-4-(5-(4- (((R)-1- cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-3-yl)-1,3,4- thiadiazol-2-yl)cyclohexyl)cyclo- propanecarboxamide

161 497.337 2 (S)-7-(5-(5-(3,3- difluoro-4- hydroxypiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

162 497.475 2 (R)-7-(5-(5-(3,3- difluoro-4- hydroxypiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

163 486.281 2 7-(4-(isopropylamino)- 5-(5-(7-oxa-2,6-diazaspiro[3.4]octan-2- yl)-1,3,4-thiadiazol-2- yl)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

164 486.309 2 7-(4-(isopropylamino)- 5-(5-(5-oxa-2,6-diazaspiro[3.4]octan-2- yl)-1,3,4-thiadiazol-2- yl)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

165 542.516 2 N-((1R,5S,9r)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.3.1]nonan- 9-yl)acetamide

166 542.472 2 N-((1R,5S,9s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.3.1]nonan- 9-yl)acetamide

167 483.323 2 7-(5-(5-(2,2- difluoromorpholino)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

168 538.327 2 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)-3,3-difluoropiperidin-4- yl)acetamide

169 538.324 2 (S)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)-3,3-difluoropiperidin-4- yl)acetamide

170 528.436 2 N-(2-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-2-azaspiro[3.4]octan- 6-yl)acetamide

171 570.466 2 N-((1R,5S,8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- ((tetrahydro-2H-pyran- 4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)-3- azabicyclo[3.2.1]octan- 8-yl)acetamide

172 529.475 2 7-(5-(5-(4-hydroxy-4- (trifluoromethyl)piperidin-1-yl)-1,3,4-thiadiazol- 2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

173 514.334 2 N-((1R,5S,6s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.1.1]heptan- 6-yl)acetamide

174 525.277 27 N-((1R,5S,6S)-3-(5-(4- (((R)-1- cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7- yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.1.1]heptan- 6-yl)acetamide

175 542.297 2 N-((1R,5S,6s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((3- methyloxetan-3- yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.1.1]heptan- 6-yl)acetamide

176 486.270 2 N-((1R,5S,6s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (methylamino)pyridin-3- yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.1.1]heptan- 6-yl)acetamide

177 501.284 2 7-(5-(5-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2- yl)-4-((tetrahydro-2H- pyran-4-yl)amino)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

178 470.211 27 7-(5-(5-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2- yl)-4-(((R)-1- cyanoethyl)amino)pyridin-2-yl)pyrrolo[1,2-b] pyridazine-3- carbonitrile

179 528.342 2 N-((1R,5S,6s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3- ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.1.1]heptan- 6-yl)acetamide

180 486.255 27 (R)-7-(4-((1- cyanoethyl)amino)-5-(5- (4-hydroxy-4-methylpiperidin-1-yl)- 1,3,4-thiadiazol-2- yl)pyridin-2- yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

181 503.309 2 7-(5-(5-(4-hydroxy-4- methylpiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- ((3-methyloxetan-3- yl)amino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

182 544.553 2 N-((1R,5S,9r)-7-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3-oxa-7- azabicyclo[3.3.1]nonan- 9-yl)acetamide

183 552.285 2 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(oxetan-3- ylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-3,3-difluoropiperidin-4- yl)acetamide

184 542.307 2 N-((1R,5S,8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3- ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1]octan- 8-yl)acetamide

185 495.220 1 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)phenyl)acetamide

186 493.590 2 7-(5-(5-((3S,4R)-3- fluoro-4-hydroxy-4-methylpiperidin-1-yl)- 1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

187 489.289 2 7-(5-(5-(4-hydroxy-4- methylpiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (oxetan-3- ylamino)pyridin-2- yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

188 517.625 2 7-(5-(5-(4-hydroxy-4- methylpiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- ((tetrahydro-2H-pyran- 4-yl)amino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

189 493.358 2 7-(5-(5-(4- (fluoromethyl)-4- hydroxypiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

190 493.432 2 7-(5-(5-((3S,4S)-3- fluoro-4-hydroxy-4-methylpiperidin-1-yl)- 1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

191 493.288 2 7-(5-(5-((3R,4R)-3- fluoro-4-hydroxy-4-methylpiperidin-1-yl)- 1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

192 493.345 2 7-(5-(5-((3R,4S)-3- fluoro-4-hydroxy-4-methylpiperidin-1-yl)- 1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

193 544.573 2 N-((1R,5S)-7-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3-oxa-7- azabicyclo[3.3.1]nonan- 9-yl)acetamide

194 519.561 1 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)-4-fluorocyclohexyl) acetamide

Procedure 28: Examples 195 and 196:

N-(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-4-fluorocyclohexyl)acetamide(Example 195 and 196)

N-(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-4-fluorocyclohexyl)acetamide(Examples 195 and 196): To a vial was added7-(5-bromo-4-(oxetan-3-ylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(30 mg, 0.081 mmol),N-(4-fluoro-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide (I-31) (40 mg,0.162 mmol), Pd(OAc)₂ (4.5 mg, 0.02 mmol), Xantphos (23.5 mg, 0.04mmol), copper(I) iodide (7.7 mg, 0.04 mmol), and cesium carbonate (80mg, 0.24 mmol). 1,4-Dioxane (0.75 mL) and DMF (0.25 mL) was added, andthe mixture was degassed with argon for 1 minute. The vial was sealedand stirred 1 hour at 105° C. Afterward, the vial was cooled and thecrude material was diluted with DMF (0.5 mL). This mixture was filtered,and purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield theproducts Example 195 Isomer 1 and Example196 Isomer 2 as separableisomers. Isomers isolated as a trifluoroacetate salt.

Isomer 1 (Example 195): ES/MS: 533.319 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.81 (d, J=2.2 Hz, 1H),8.75 (d, J=2.2 Hz, 1H), 8.10 (d, J=5.1 Hz, 1H), 7.75 (s, 1H), 7.27 (d,J=5.1 Hz, 1H), 5.38-5.26 (m, 1H), 5.22 (q, J=6.8, 6.1 Hz, 2H), 4.83 (dd,J=6.9, 5.6 Hz, 2H), 3.98-3.85 (m, 1H), 2.50-2.22 (m, 2H), 2.04 (d,J=14.2 Hz, 4H), 1.98 (s, 3H), 1.86-1.70 (m, 2H).

Isomer 2 (Example 196): ES/MS: 533.297 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.88 (s, 1H), 8.80 (d, J=2.2 Hz, 1H),8.75 (d, J=2.1 Hz, 1H), 8.10 (d, J=5.1 Hz, 1H), 7.77 (s, 1H), 7.26 (d,J=5.1 Hz, 1H), 5.38-5.26 (m, 1H), 5.26-5.19 (m, 2H), 4.82 (dd, J=6.9,5.5 Hz, 2H), 4.09-3.99 (m, 1H), 2.53 (dddd, J=23.8, 13.7, 9.2, 4.2 Hz,2H), 2.35-2.19 (m, 2H), 2.09 (ddd, J=14.3, 9.3, 4.6 Hz, 2H), 2.00 (s,3H), 1.98-1.81 (m, 2H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Structure # m/z Procedure Name

197 521.207 14 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cuban-1-yl)acetamide

198 543.299 1 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(oxetan-3- ylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4- yl)acetamide

199 446.248 1 7-(5-(5-((1s,3s)-3- hydroxy-3- methylcyclobutyl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

200 460.223 1 7-(5-(5-((1s,3s)-3- hydroxy-3- methylcyclobutyl)-1,3,4-thiadiazol-2-yl)-4- (oxetan-3- ylamino)pyridin-2- yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

201 515.303 1 N-((1r,3r)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- ((tetrahydro-2H-pyran-4- yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclobutyl)acetamide

202 487.235 1 N-((1r,3r)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3- ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclobutyl)acetamide

203 541.317 1 N-((1s,4s)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3- ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)cyclopropane- carboxamide

204 535.300 2 7-(5-(5-((3S,4S)-3- fluoro-4-hydroxy-4-methylpiperidin-1-yl)- 1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4- yl)amino)pyridin-2- yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

205 531.455 1 methyl ((1s,4s)-4-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3- ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)carbamate

Procedure 29: Example 206:

7-(5-(5-(4-hydroxy-4-methylcyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(oxetan-3-ylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 206)

7-(5-(5-(4-hydroxy-4-methylcyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(oxetan-3-ylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 206 from Isomer 1): A microwave vial was charged with4-(5-(6-chloro-4-(oxetan-3-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-1-methylcyclohexan-1-ol(1-34 Isomer 1) (21.1 mg, 0.055 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(1-8, 20.9 mg, 0.078 mmol), and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.2 mg, 0.011 mmol). To the flask was added DME(1.0 mL) and a 2M aqueous solution of sodium carbonate (0.06 mL, 0.11mmol). The reaction mixture was degassed by bubbling argon for 30seconds. The vial was sealed and heated with stirring at 120° C. for 20minutes in a microwave reactor. The cooled reaction mixture wasconcentrated and purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) toyield the product Example 206 from Isomer 1 as a trifluoroacetate salt.

ES/MS: 488.296 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.80-8.76 (m, 2H), 8.72 (d, J=2.2 Hz,1H), 8.07 (d, J=5.0 Hz, 1H), 7.78 (s, 1H), 7.24 (d, J=5.1 Hz, 1H),5.30-5.19 (m, 3H), 4.86-4.78 (m, 2H), 3.45-3.36 (m, 1H), 2.35-2.20 (m,2H), 1.99-1.78 (m, 4H), 1.78-1.64 (m, 2H), 1.31 (s, 3H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z cedure Name

207 507.278 2 7-(5-(5-((3S,4S)- 3-fluoro-4- hydroxy-4- methylpiperidin-1-yl)-1,3,4-thiadiazol- 2-yl)- 4-(oxetan-3- ylamino)pyridin-2-yl)pyrrolo[1,2-b] pyridazine- 3-carbonitrile

208 488.296 29 7-(5-(5-((1s,4s)- 4-hydroxy- 4-methylcyclohexyl)- 1,3,4-thiadiazol-2-yl)- 4-(oxetan-3- ylamino)pyridin-2- yl)pyrrolo[1,2-b]pyridazine- 3-carbonitrile

209 544.340 2 N-((1R,5S,7r)- 9-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl)- 3-oxa-9-azabicyclo [3.3.1]nonan-7- yl)acetamide

210 600.357 2 N-((1R,5S,8s)- 3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((3- methyloxetan-3- yl)amino)pyridin-3-yl)-1,3,4-thiadiazol- 2-yl)-3-azabicyclo [3.2.1]octan-8-yl)-2-hydroxy-2- methylpropanamide

211 362.172 6 7-(4- (isopropylamino)-5- (1,3,4-thiadiazol-2-yl)pyridin-2-yl) pyrrolo[1,2- b]pyridazine-3- carbonitrile

212 405.209 8 7-(5-(5-(2- aminoethyl)- 1,3,4-thiadiazol-2-yl)-4-(isopropylamino) pyridin-2- yl)pyrrolo[1,2-b] pyridazine-3-carbonitrile

213 475.211 5 5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-N- ((1r,3r)-3- hydroxycyclobutyl)-1,3,4-thiadiazole- 2-carboxamide

214 489.324 5 (R)-7-(5-(5-(2- (hydroxymethyl) pyrrolidine-1-carbonyl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo [1,2-b]pyridazine- 3-carbonitrile

215 475.210 5 5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-N- ((1s,3s)-3- hydroxycyclobutyl)-1,3,4-thiadiazole- 2-carboxamide

216 489.272 5 (R)-7-(5-(5-(3- (hydroxymethyl) pyrrolidine-1-carbonyl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino) pyridin-2-yl)pyrrolo[1,2-b] pyridazine- 3-carbonitrile

217 489.322 5 (S)-7-(5-(5-(2- (hydroxymethyl) pyrrolidine-1-carbonyl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino) pyridin-2-yl)pyrrolo[1,2-b] pyridazine- 3-carbonitrile

218 489.313 5 5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3- yl)-N-((1s,3s)-3- hydroxy-3-methylcyclobutyl)- 1,3,4-thiadiazole-2- carboxamide

219 489.376 5 5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3- yl)-N-((1r,3r)-3- hydroxy-3-methylcyclobutyl)- 1,3,4- thiadiazole-2- carboxamide

220 503.284 5 5-(6-(3- cyanopyrrolo[1,2- b]pyridazin- 7-yl)-4-(isopropylamino) pyridin-3- yl)-N-((1r,4r)-4- hydroxycyclohexyl)-1,3,4-thiadiazole- 2-carboxamide

221 489.261 5 (S)-7-(5-(5-(3- (hydroxymethyl) pyrrolidine-1-carbonyl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino) pyridin-2-yl)pyrrolo[1,2-b] pyridazine- 3-carbonitrile

222 574.235 5 tert-butyl (R)-(1- (5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazole-2- carbonyl)pyrrolidin-3- yl)carbamate

223 574.237 5 tert-butyl (S)-(1- (5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazole-2- carbonyl)pyrrolidin- 3-yl)carbamate

224 503.254 5 5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3- yl)-N-((1s,4s)-4- hydroxycyclohexyl)-1,3,4-thiadiazole- 2-carboxamide

225 588.337 5 tert-butyl (S)- (1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazole-2- carbonyl)piperidin-3- yl)carbamate

226 588.345 5 tert-butyl (S)- ((1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazole-2- carbonyl)pyrrolidin-2- yl)methyl)carbamate

227 657.3  1 N-((1R,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (((1r,4R)-4-(1- (difluoromethyl)-1H- pyrazol-4-yl)cyclohexyl)amino) pyridin- 3-yl)-1,3,4-thiadiazol- 2-yl)cyclohexyl)acetamide

228 588.254 5 tert-butyl (R)- ((1-((5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazole-2- carbonyl)pyrrolidin-2- yl)methyl)carbamate

Procedure 31: Example 229:

(S)-7-(5-(5-(2-(aminomethyl)pyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 229)

tert-butyl(S)-((1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-2-yl)methyl)carbamate:To a solution of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate(50.0 mg, 0.16 mmol) in MeOH (0.5 mL) was added tert-butyl(S)-(pyrrolidin-2-ylmethyl)carbamate (38.4 mg, 0.19 mmol). The reactionmixture was heated at 80° C. for 1 hour, then concentrated in vacuo andpurified by silica gel column chromatography (eluent: MeOH/DCM) toprovide tert-butyl(S)-((1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-2-yl)methyl)carbamate.

ES/MS: 481.6 [M+H⁺].

tert-butyl(S)-((1-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-2-yl)methyl)carbamate:A solution of tert-butyl(S)-((1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-2-yl)methyl)carbamate(40.7 mg, 0.084 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(27.3 mg, 0.10 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.3 mg,0.021 mmol), and sodium carbonate (2N in water, 85 μL, 0.17 mmol) in1,4-dioxane (0.71 mL) was sparged with argon for 60 seconds, then heatedin a microwave reactor at 125° C. for 20 minutes. Upon cooling, thereaction mixture was filtered and purified by reverse phase highpressure liquid chromatography (eluent: water/MeCN*0.1% TFA) to providetert-butyl(S)-((1-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-2-yl)methyl)carbamate.

ES/MS: 588.2 [M+H⁺].

(S)-7-(5-(5-(2-(aminomethyl)pyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 229): To a solution of tert-butyl(S)-((1-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-2-yl)methyl)carbamate(19 mg, 0.032mmo1) in dioxane (0.25 mL) was added hydrochloric acid (4Nin dioxane, 121.2 μL, 0.48 mmol) and stirred for 3 hours. The reactionmixture was concentrated, filtered and purified by reverse phase highpressure liquid chromatography (eluent: water/MeCN*0.1% TFA) to providethe final compound Example 229.

ES/MS: 488.2 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.84 (d, J=5.6 Hz, 1H), 8.76 (d, J=2.2Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.13 (s, 1H), 8.06 (d, J=5.0 Hz, 1H),7.24 (d, J=5.0 Hz, 1H), 4.61 (dd, J=8.4, 4.2 Hz, 1H), 4.42-4.18 (m, 3H),3.29-3.20 (m, 1H), 2.35-2.08 (m, 4H), 1.94 (dq, J=11.1, 5.2, 4.7 Hz,1H), 1.52 (d, J=6.4 Hz, 6H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z cedure Name

230 488.268 31 (R)-7-(5-(5-(2- (aminomethyl)pyrrolidine-1-carbonyl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2-b] pyridazine-3- carbonitrile

231 514.4  2 N-(2-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)-2-azaspiro[3.3]heptan-6- yl)acetamide

232 (M + H) 488.3  2 7-(5-(5-(4- acetylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

233 (M + H) 459.4  2 7-(5-(5-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

234 (M + H) 459.4  2 7-(5-(5-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

235 (M + H) 473.6  2 7-(5-(5-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

236 (M + H) 473.4  2 7-(5-(5-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino) pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

237 (M + H) 459.4  2 7-(5-(5-((1R,4R)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2-b] pyridazine-3- carbonitrile

238 (M + H) 459.3  2 7-(5-(5-((1S,4S)-2-oxa- 5- azabicyclo[2.2.1]heptan-5-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

239 (M + H) 500.3  2 N-((1R,5S,6r)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.1.0]hexan- 6-yl)acetamide

240 (M + H) 500.3  2 N-((1R,5S,6s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.1.0]hexan- 6-yl)acetamide

241 583.614 1 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4- hydroxybicyclo[2.2.2] octan-1-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)acetamide

242 502.509 5 (S)-7-(5-(5-(2- (aminomethyl)pyrrolidine-1-carbonyl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2-b] pyridazine-3- carbonitrile

243 543.597 1 N-((1R,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (((1s,3S)-3-hydroxy-3- methylcyclobutyl)amino)pyridin-3-yl)-1,3,4- thiadiazol-2- yl)cyclohexyl)acetamide

244 555.286 1 N-((1R,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (((1s,4S)-4- hydroxycyclohexyl)amino)pyridin-3-yl)-1,3,4- thiadiazol-2- yl)cyclohexyl)acetamide

245 557.575 1 N-((1S,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (((1S,3R)-3- hydroxycyclohexyl)amino)pyridin-3-yl)-1,3,4- thiadiazol-2- yl)cyclohexyl)acetamide

246 485.515 1 N-(3-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[1.1.1]pentan- 1-yl)acetamide

247 487.644 1 N-((1S,3S)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclopentyl)acetamide

248 487.635 1 N-((1R,3S)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclopentyl)acetamide

249 516.638 2 N-((2S)-1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-2-methylpiperidin-4- yl)acetamide

250 520.576 2 N-((3S,4R)-1-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3-fluoropiperidin-4- yl)acetamide

251 538.530 2 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)-3,3-difluoropiperidin-4- yl)acetamide

252 459.349 2 7-(5-(5-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

253 599.408 1 methyl ((1r,4r)-4-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4- hydroxybicyclo[2.2.2] octan-1-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)carbamate

254 637.421 2 methyl (((1r,3r)-3-((5- (5-(4-acetamido-3,3-difluoropiperidin-1-yl)- 1,3,4-thiadiazol-2-yl)-2- (3-cyanopyrrolo[1,2-b]pyridazin-7- yl)pyridin-4-yl)amino) cyclobutyl) methyl)carbamate

255 543.38  1 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- ((tetrahydro-2H-pyran- 4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)acetamide

256 515.41  2 7-(5-(5-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2- yl)-4-((tetrahydro-2H- pyran-4-yl)amino)pyridin-2- yl)pyrrolo[1,2-b] pyridazine-3- carbonitrile

257 495.24  2 7-(5-(5-(1,1- dioxidothiomorpholino)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

258 500.31  20 7-(5-(5-(6-acetyl-3,6- diazabicyclo[3.1.1]heptan-3-yl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

259 514.36  2 7-(5-(5-(8-acetyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

260 514.33  2 7-(5-(5-(3-acetyl-3,8- diazabicyclo[3.2.1]octan-8-yl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

261 500.30  20 7-(5-(5-(3-acetyl-3,6- diazabicyclo[3.1.1]heptan-6-yl)-1,3,4-thiadiazol- 2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

262 494.22  2 7-(5-(5-(1-imino-1- oxido-1l6- thiomorpholino)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

263 540.41  16 7-(5-(5-(8- (cyclopropanecarbonyl)- 3,8-diazabicyclo[3.2.1]octan- 3-yl)-1,3,4-thiadiazol-2- yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

264 542.34  2 7-(5-(5-(8-acetyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2- yl)-4-((3-methyloxetan- 3-yl)amino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

265 530.28  18 7-(5-(5-((1R,5S)-9- acetyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan- 7-yl)-1,3,4-thiadiazol- 2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

266 530.42  2 7-(5-(5-((1R,5S)-7- acetyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan- 9-yl)-1,3,4-thiadiazol- 2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

267 500.27  2 7-(5-(5-acetyl-2,5- diazabicyclo[4.1.0]heptan-2-yl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

268 557.30  1 N-((1r,4r)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4- methyltetrahydro-2H- pyran-4-yl)amino)pyridin-3-yl)- 1,3,4-thiadiazol-2- yl)cyclohexyl)acetamide

269 572.30  18 7-(5-(5-((1R,5S)-9- acetyl-3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-1,3,4- thiadiazol-2-yl)-4- ((tetrahydro-2H-pyran-4-yl)amino)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

270 527.31  1 N-(3-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran- 4-yl)amino)pyridin-3- yl)-1,3,4-thiadiazol-2-yl)bicyclo[1.1.1]pentan- 1-yl)acetamide

271 558.51  2 tert-butyl 3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3,6- diazabicyclo[3.1.1]heptane- 6-carboxylate

272 584.56  2 N-((1R,5S,8s)-3-(5-(6- (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4- methyltetrahydro-2H- pyran-4-yl)amino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8- yl)acetamide

273 544.37  19 7-(5-(5-(6-(2-hydroxy-2- methylpropanoyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)-1,3- thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b] pyridazine-3- carbonitrile

274 458.49  19 7-(5-(5-(3,6- diazabicyclo[3.1.1] heptan-6-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

275 544.58  19 7-(5-(5-(3-(2-hydroxy-2- methylpropanoyl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl)-1,3,4-thiadiazol- 2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

276 591.31  19 7-(5-(5-(3-(2- ((dimethyl(oxo)-l6- sulfanylidene)amino)acetyl)-3,6- diazabicyclo[3.1.1] heptan-6-yl)-1,3,4- thiadiazol-2-yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

277 584.35  20 7-(4-(isopropylamino)- 5-(5-(3-(4- methylpiperazine-1-carbonyl)-3,6- diazabicyclo[3.1.1] heptan-6-yl)-1,3,4-thiadiazol-2-yl)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

278 473.39  14 N-((1r,3r)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl)acetamide

279 473.4  14 N-((1s,3s)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl)acetamide

280 527.66  14 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1- yl)acetamide

Procedure 32: Example 281:

N-((1s,3s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl)cyclopropanecarboxamide(Example 281)

7-(5-(5-((1r,3r)-3-aminocyclobutyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride: tert-butyl((1r,3r)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl)carbamate(150 mg, 0.28 mmol) was then dissolved in HCl (4.0M in dioxane, 2 mL, 8mmol) and stirred at room temperature for 1 hour after which thereaction mixture was concentrated to dryness directly to give thedesired product as an HCl salt which was used without furtherpurification.

ES/MS: 431.3 [M+H]⁺

N-((1s,3s)-3-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl)cyclopropanecarboxamide(Example 281): A flask of Cyclopropane carboxylic acid (12 mg, 0.14mmol), DIPEA (39 mg, 0.3 mmol) and HATU (61.5 mg, 0.16 mmol) wasdissolved in DMF (1 mL),7-(5-(5-((1r,3r)-3-aminocyclobutyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (50 mg, 0.11 mmol) was added to the solution. It wasstirred for 20 minutes. This mixture was filtered, and purified byRP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product Example 281as a trifluoroacetate salt.

ES/MS: 499.4 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.68 (s, 1H), 8.57 (t, J=1.9 Hz, 2H),8.05-7.91 (m, 2H), 7.17 (d, J=5.1 Hz, 1H), 4.64 (p, J=8.0 Hz, 1H), 4.18(p, J=6.5 Hz, 1H), 4.02 (dt, J=9.5, 4.8 Hz, 1H), 2.78 (ddd, J=12.6, 7.6,4.0 Hz, 2H), 2.67 (td, J=12.8, 11.2, 8.3 Hz, 2H), 1.49 (d, J=6.4 Hz,7H), 0.87 (p, J=4.2 Hz, 2H), 0.74 (dq, J=7.4, 4.3, 3.9 Hz, 2H).

Example 282 was made according to Procedure 14, using the appropriatestarting materials and protecting group chemistry as needed:

ES/MS Structure # m/z Procedure Name

282 445.29 14 N-((1r,3r)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (methylamino)pyridin- 3-yl)-1,3,4- thiadiazol-2-yl)cyclobutyl) acetamide

Procedure 33: Example 283:

7-(4-(isopropylamino)-5-(5-((1r,3r)-3-(oxetan-3-ylamino)cyclobutyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 283)

7-[4-(isopropylamino)-5-[5-[rac-(2R)-2-(aminomethyl)pyrrolidine-1-carbonyl]-1,3,4-thiadiazol-2-yl]-2-pyridyl]pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 283): To a solution of7-(5-(5-((1r,3r)-3-aminocyclobutyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (30 mg, 0.064 mmol), oxetan-3-one (32.4 mg, 0.45 mmol) in1 mL of DCE and 1 mL of acetic acid, sodium triacetoxy borohydride (95.3mg, 0.45 mmol) was added to the suspension. It was stirred forovernight. Oxetan-3-one (32.4 mg, 0.45 mmol) and sodium triacetoxyborohydride (95.3 mg, 0.45 mmol) was added to the mixture. After 5hours, diluted with EtOAc (20 mL) and washed with 10 mL of saturatedNaHCO₃. The organic layer was dried and concentrated. This mixture wasfiltered, and purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yieldthe product Example 283 as a trifluoroacetate salt. ES/MS: 487.6 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=2.2 Hz, 1H), 8.72 (s, 1H),8.67 (d, J=2.2 Hz, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.99 (s, 1H), 7.23 (d,J=5.1 Hz, 1H), 4.93 (t, J=7.5 Hz, 2H), 4.68 (dd, J=8.0, 5.2 Hz, 2H),4.44 (h, J=6.1, 5.6 Hz, 1H), 4.31 (p, J=6.6 Hz, 1H), 4.23 (q, J=6.9 Hz,1H), 4.20-4.09 (m, 1H), 2.89 (t, J=7.5 Hz, 4H), 1.48 (d, J=6.4 Hz, 6H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z cedure Name

284 513.48  14  N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.1]heptan-1- yl)acetamide

285 513.5  14  N-(5-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.1]heptan-2- yl)acetamide

286 447.36  2 7-(5-(5-(3-hydroxy-3- methylazetidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

287 475.4  2 7-(5-(5-(4-hydroxy-4- methylpiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

288 499.34  14  N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.1.1]hexan-1- yl)acetamide

289 487.55  14  N-(((1s,3s)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl)methyl) acetamide

290 487.54  14  N-(((1r,3r)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl)methyl) acetamide

291 471.584 2 7-(5-(5-(3- azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2-yl)- 4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

292 500.370 2 N-((1R,5S,8s)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (methylamino)pyridin-3- yl)-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan- 8-yl)acetamide

293 459.370 2 7-(5-(5-(1-oxa-6- azaspiro[3.3]heptan-6-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

294 481.571 2 7-(5-(5-(4,4- difluoropiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

295 485.636 2 7-(5-(5-(3- azabicyclo[3.3.1]nonan-3-yl)-1,3,4-thiadiazol-2-yl)- 4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

296 502.399 2 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)piperidin-3-yl)acetamide

297 501.294 2 7-(5-(5-(3-hydroxy-3- (trifluoromethyl)azetidin-1-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

298 516.461 2 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)azepan-4-yl)acetamide

299 502.535 2 (S)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)piperidin-3-yl)acetamide

300 542.388 2 N-((1R,5S,8s)-3-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-3- azabicyclo[3.2.1]octan-8- yl)-N-methylacetamide

301 556.449 2 7-(4-(isopropylamino)-5- (5-((1R,5S,8s)-8-(2-oxooxazolidin-3-yl)-3- azabicyclo[3.2.1]octan-3- yl)-1,3,4-thiadiazol-2-yl)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

302 500.352 2 7-(5-(5-((1S,4S)-5-acetyl- 2,5- diazabicyclo[2.2.1]heptan-2-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

303 500.367 2 7-(5-(5-((1R,4R)-5-acetyl- 2,5- diazabicyclo[2.2.1]heptan-2-yl)-1,3,4-thiadiazol-2- yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

304 502.364 2 7-(4-(isopropylamino)-5- (5-(4-(oxetan-3-yl)piperazin-1-yl)-1,3,4- thiadiazol-2-yl)pyridin-2- yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

305 502.319 2 1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)-N-methylpiperidine-4- carboxamide

306 510.262 2 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(methylamino)pyridin-3- yl)-1,3,4-thiadiazol-2-yl)-3,3-difluoropiperidin-4- yl)acetamide

307 510.267 2 (S)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(methylamino)pyridin-3- yl)-1,3,4-thiadiazol-2-yl)-3,3-difluoropiperidin-4- yl)acetamide

308 564.424 2 7-(4-(isopropylamino)-5- (5-((1R,5S,8s)-8-(pyrimidin-2-ylamino)-3- azabicyclo[3.2.1]octan-3-yl)-1,3,4-thiadiazol-2- yl)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3-carbonitrile

309 581.515 2 7-(5-(5-((1R,5S,8s)-8-((3- fluoropyridin-2-yl)amino)-3-azabicyclo[3.2.1]octan- 3-yl)-1,3,4-thiadiazol-2- yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

310 470.377 2 7-(5-(5-(4-cyanopiperidin- 1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3-carbonitrile

311 559.450 1 N-((1s,4s)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (oxetan-3- ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl)-2-hydroxy- 2-methylpropanamide

312 545.697 1 N-((1s,4s)-4-(5-(6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-hydroxy- 2-methylpropanamide

313 499.585 18  N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)cyclohex-3-en-1-yl)acetamide

Procedure 34: Example 314:

N-((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-3-methyloxetane-3-carboxamide(Example 314)

Tert-butyl((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate:To a slurry of tert-butyl((1r,4r)-4-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate(prepared following the protocol in steps 1 and 2 of Procedure 14 usingthe appropriate carboxylic acid) (89 mg, 0.20 mmol) in DME (3 mL) wasadded7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(85 mg, 0.32 mmol), XPhos Pd G3 (12 mg, 0.15 mmol) and aqueous potassiumphosphate, tribasic (2M, 0.2 mL, 0.4 mmol). The resulting mixture wasdegassed with argon for 2 min, sealed, and heated in a microwave at 120°C. for 20 min. The resulting slurry was diluted with Et₂O, filtered, andwashed with Et2O. The resulting solid was purified by silica gelchromatography (eluent: MeOH/CH₂Cl₂) to give the desired product.

ES/MS: 559.605 [M+H]⁺

7-(5-(5-((1R,4R)-4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile:To a solution of tert-butyl((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate(75 mg, 0.13 mmol) in CH₂Cl₂ (2.5 mL) was added solution of hydrochloricacid in dioxane (4M, 0.5 mL, 2 mmol). The resulting slurry was stirredat 50° C. for 1 hour. Additional hydrochloric acid in dioxane (4M, 0.5mL, 2 mmol) and methanol (0.5 mL) was added and the solution was stirredat 50° C. for 2 hours, followed by stirring at room temperature for 18hours. The reaction mixture was concentrated and the crude product wasused directly in the next step.

ES/MS: 459.622 [M+H]⁺

N-((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-3-methyloxetane-3-carboxamide(Example 314): To a slurry of7-(5-(5-((1R,4R)-4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilein DMF (0.8 mL) and MeOH (0.5 mL) was added N,N-diisopropylethylamine(0.06 mL, 0.34 mmol),3-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]propanoic acid(18 mg, 0.056 mmol), and HATU (20 mg, 0.053 mmol). The solution wasstirred at room temperature for 16 hours and concentrated. The crudematerial was dissolved in D1VIF and purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product Example 314 as atrifluoroacetate salt.

ES/MS: 557.537 [M+H]⁺

1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J=2.2 Hz, 1H), 8.74 (s, 1H),8.71 (d, J=2.1 Hz, 1H), 8.10 (d, J=5.1 Hz, 1H), 7.97 (s, 1H), 7.88 (d,J=7.8 Hz, 1H), 7.26 (d, J=5.1 Hz, 1H), 4.42 (d, J=6.1 Hz, 2H), 4.34 (p,J=6.4 Hz, 1H), 3.93-3.77 (m, 1H), 2.35 (d, J=13.0 Hz, 2H), 2.12 (d,J=12.6 Hz, 2H), 1.84 (qd, J=13.1, 3.4 Hz, 3H), 1.62 (s, 3H), 1.51 (d,J=6.4 Hz, 8H). Additional peak obscured by solvent.

Example 315 was made according to Procedure 34, using the appropriatestarting materials and protecting group chemistry as needed:

ES/MS Structure # m/z Procedure Name

315 545.530 34 N-((1r,4r)-4-(5- (6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-4- (isopropylamino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl) cyclohexyl)-2- hydroxy-2- methylpropanamide

Procedure 35: Example 316:

N-((1R,4r)-4-(5-(4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide(Example 316)

(R)-2-((2-chloro-5-iodopyridin-4-yl)amino)propanenitrile: To a solutionof (R)-2-((2-chloro-5-iodopyridin-4-yl)amino)propanamide (10.1 g, 30mmol) in methyl-THF (165 mL) was added trimethylamine (21 mL, 154 mmol).To the slurry was slowly added trifluoroacetic anhydride (1.15 mL, 8.27mmol) in methyl-THF (10 mL) over 15 min. The resulting solution isstirred at room temperature for 45 min before dilution with H₂O andwashing with aqueous

NH4Cl. The aqueous layers are back-extracted with ethyl acetate and thecombine organic layers are dried over MgSO4 and concentrated to dryness.The crude material was dissolved in hot ethyl acetate, to which hexaneswas added until precipitation initiated. The solution was allowed tocool to room temperature for 18 hours and the resulting precipitate wasfiltered and washed with hexanes to provide the desired product.

ES/MS: 308.052 [M+H]⁺

N-((1R,4r)-4-(5-(6-chloro-4-(((R)-1-cyanoethyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide:To a solution of(R)-2-((2-chloro-5-iodopyridin-4-yl)amino)propanenitrile (80 mg, 0.26mmol) in dioxane (3.3 mL) was addedN-((1r,4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide (62 mg, 0.27mmol), Palladium acetate (9 mg, 0.04 mmol),9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (50 mg, 0.08 mmol),Copper(i) iodide (20 mg, 0.08 mmol), and cesium carbonate (108 mg, 0.33mmol). The reaction mixture was degassed with argon for 3 min, sealed,and heated to 100° C. for 1.5 hours. The reaction mixture was purifiedby RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the desired product asa trifluoroacetate salt.

ES/MS: 405.213 [M+H]⁺

N-((1R,4r)-4-(5-(4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide(Example 316): To a solution ofN-((1R,4r)-4-(5-(6-chloro-4-(((R)-1-cyanoethyl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)acetamide(6 mg, 0.012 mmol) in DME (0.5 mL) was added7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(6 mg, 0.023 mmol), XPhos Pd G3 (3 mg, 0.0035 mmol) and aqueouspotassium phosphate, tribasic (2M, 0.023 mL, 0.01 mmol). The resultingmixture was degassed with argon for 2 min, sealed, and heated in amicrowave at 120° C. for 15 min. The reaction mixture was diluted withDMF and purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield theproduct Example 316 as a trifluoroacetate salt.

ES/MS: 512.397 [M+H]⁺

1H NMR (400 MHz, Methanol-d4) δ 8.83 (s, 1H), 8.73 (d, J=2.1 Hz, 1H),8.67 (d, J=2.1 Hz, 1H), 8.23 (s, 1H), 8.08 (d, J=5.0 Hz, 1H), 7.22 (d,J=5.1 Hz, 1H), 5.20 (q, J=6.9 Hz, 1H), 3.75 (ddq, J=12.1, 7.8, 4.2 Hz,1H), 2.31 (d, J=13.2 Hz, 1H), 2.09 (d, J=12.3 Hz, 2H), 1.94 (s, 3H),1.91 (d, J=6.9 Hz, 3H), 1.80 (qd, J=12.7, 2.4 Hz, 3H), 1.47 (qd, J=12.9,12.4, 2.9 Hz, 3H).

Procedure 36: Example 317:

7-(5-(5-(3-hydroxy-3-(methyl-d3)butyl-4,4,4-d3)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 317)

4-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-(methyl-d3)butan-1,1,1-d3-2-ol:To a flask with methyl3-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanoate(100 mg, 0.29 mmol) under N₂ was added THF (2 mL), and the reaction wascooled to 0° C. To the reaction was added Methyl-d3-lithium, as complexwith lithium iodide solution (117 mg, 0.73 mmol) dropwise, and thereaction was stirred for 30 min at 0° C. . Afterward, the reaction wasquenched by dropwise addition of saturated aqueous NH₄Cl, and themixture was diluted with EtOAc and water. The layers were separated, andthe aqueous layer was washed once with EtOAc. The combined organiclayers were dried over MgSO₄, filtered and concentrated. The resultingcrude residue was purified by silica gel chromatography (eluent:EtOAc/hexanes) to give the desired product.

ES/MS: 347.27[M+H]⁺

7-(5-(5-(3-hydroxy-3-(methyl-d3)butyl-4,4,4-d3)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 317): Coupling performed as in Procedure 9 to yield the productExample 317 as a trifluoroacetate salt.

ES/MS: 454.59 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.81-8.62 (m, 3H), 8.07 (d, J=5.1 Hz,1H), 7.95 (s, 1H), 7.23 (d, J=5.1 Hz, 1H), 4.31 (hept, J=6.3 Hz, 1H),3.33 (d, J=6.0 Hz, 2H), 2.12-1.97 (m, 2H), 1.49 (d, J=6.4 Hz, 6H).

Example 318 was made according to Procedure 9, using the appropriatestarting materials and protecting group chemistry as needed:

ES/MS Structure # m/z Procedure Name

318 448.53 9 ethyl 2-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3- yl)-1,3,4-thiadiazol-2- yl)acetate

Procedure 37: Example 319:

2-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)aceticacid (Example 319)

2-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)aceticacid (Example 319): To ethyl2-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridin-3-yl)-1,3 ,4-thiadiazol-2-yl)acetate (10 mg, 0.022mmol) in THF (0.5 mL) was added lithium hydroxide (3 mg, 0.125 mmol).The reaction mixture was stirred at RT for 6 hours then directlypurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productExample 319 as a trifluoroacetate salt.

ES/MS: 420.19 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 9.58 (s, 1H), 8.87-8.74 (m, 2H), 8.68(d, J=2.1 Hz, 1H), 8.13-7.92 (m, 2H), 7.22 (d, J=5.1 Hz, 1H), 4.42-4.25(m, 1H), 2.99 (s, 1H), 2.86 (d, J=0.8 Hz, 1H), 1.49 (dd, J=6.4, 4.8 Hz,6H).

Procedure 38: Example 320:

7-(5-(5-(2-hydroxy-2-methylpropyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 320)

1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-2-methylpropan-2-olEthyl (60 mg, 0.22 mmol) in THF (1 mL) was added lithiumdiisopropylamide (2.0M THF, 0.56 mmol). The temperature was maintainedin the range of −70° C. to −78° C. throughout the 15 minute addition.Following the addition, the resulting slurry was stirred for 2 hours atambient temperature then directly purified by RP-HPLC (eluent:water/MeCN*0.1% TFA) to yield the product7-(5-(5-(2-hydroxy-2-methylpropyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 320): Coupling performed as in Procedure 9 to yield the productExample 320 as a trifluoroacetate salt.

ES/MS: 434.36 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.82-8.74 (m, 2H), 8.68 (d, J=2.2 Hz,1H), 8.08 (d, J=5.1 Hz, 1H), 7.95 (d, J=1.9 Hz, 1H), 7.23 (d, J=5.0 Hz,1H), 4.38-4.25 (m, 1H), 3.34 (s, 2H), 1.73 (s, 1H), 1.49 (dd, J=6.5, 2.4Hz, 6H), 1.31 (s, 5H).

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Structure # m/z Procedure Name

321 401.33 9 7-(5-(5-(cyanomethyl)- 1,3,4-thiadiazol-2-yl)- 4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

322 432.35 9 7-(4-(isopropylamino)- 5-(5-(tetrahydrofuran-3-yl)-1,3,4-thiadiazol- 2-yl)pyridin-2- yl)pyrrolo[1,2- b]pyridazine-3-carbonitrile

323 514.32 2 (R)-N-(5-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)-5-azaspiro[2.4]heptan-7- yl)acetamide

324 514.32 2 (S)-N-(5-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)-5-azaspiro[2.4]heptan-7- yl)acetamide

325 428.2  2 7-(5-(5-(1H-pyrazol-1- yl)-1,3,4-thiadiazol-2- yl)-4-(isopropylamino)pyridin- 2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

326 468.26 2 7-(5-(5-(4- cyclopropyl-1H- imidazol-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino) pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

327 524.3  2 N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2-yl)-4,4-difluoropyrrolidin-3- yl)acetamide

328 522.26 2 7-(5-(5-(3-(3,3- difluoropyrrolidin-1-yl)azetidin-1-yl)-1,3,4- thiadiazol-2-yl)-4- (isopropylamino)pyridin-2-yl)pyrrolo[1,2- b]pyridazine-3- carbonitrile

329 461.27 2 (S)-7-(5-(5-(2- (hydroxymethyl) pyrrolidin-1-yl)-1,3,4-thiadiazol-2-yl)-4- (isopropylamino) pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3- carbonitrile

330 488.28 2 (R)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2- yl)pyrrolidin-3-yl)acetamide

331 488.28 2 (S)-N-(1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(isopropylamino) pyridin-3-yl)-1,3,4- thiadiazol-2- yl)pyrrolidin-3-yl)acetamide

332 503.22 2 (S)-1-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(oxetan-3- ylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)-N-methylpyrrolidine- 2-carboxamide

333 468.28 1 7-(5-(5-(4- cyanocyclohexyl)- 1,3,4-thiadiazol-2-yl)- 4-(isopropylamino) pyridin-2-yl)pyrrolo [1,2-b]pyridazine-3- carbonitrile

334 513.23 1 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(oxetan-3- ylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)bicyclo[2.1.1]hexan- 1-yl)acetamide

335 557.39 1 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(oxetan-3- ylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)bicyclo[2.1.1]hexan- 1-yl)-2-hydroxy-2- methylpropanamide

Procedure 39: Example 336:

7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 336):

methyl 6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinate: To asolution of methyl 4,6-dichloropyridine-3-carboxylate (4.00 g, 19.4mmol) and tetrahydropyran-4-amine hydrochloride (4.01 g, 29.1 mmol) inTHF (20 mL) was added N,N-diisopropylethylamine (10.1 mL, 58.2 mmol).The reaction mixture was heated to 120° C. overnight. The reaction wascooled to rt then partitioned between water and EtOAc, and the aqueouslayer was extracted two additional times with EtOAc. The combinedorganic layers were washed with brine and dried over magnesium sulfate,isolated by vacuum filtration, concentrated in vacuo, and purified bysilica gel column chromatography (eluent: EtOAc/Hexanes) to provide thedesired product.

ES/MS: 271.24 (M+H⁺)

6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinohydrazide: To asolution of methyl6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinate (3.03 g, 11.2mmol) in EtOH (18 mL) was added hydrazine hydrate (4.42 mL, 90.9 mmol).The solution was refluxed at 80° C. for 3 hours. The solution wascooled, concentrated and carried forward without further purification.

ES/MS: 271.20 (M+H⁺)

tert-butyl(4-(2-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinoyl)hydrazine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)carbamate:To a solution of crude6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinohydrazide (2.7 g,9.97 mmol) and4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (2.8g, 10.5 mmol) in DMF (50 mL) was added N,N-diisopropylethylamine (5.70mL, 31.9 mmol) followed by a solution of HATU (4.55 g, 12.0 mmol). Thereaction mixture was stirred at RT for 15 minutes, then concentrated invacuo, and purified by silica gel column chromatography (eluent:MeOH/DCM).

ES/MS: 522.89 [M+H⁺].

tert-butyl(4-(5-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate:To a solution of tert-butyl(4-(2-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinoyl)hydrazine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)carbamate(5.00 g, 9.58 mmol) in 2-methyltetrahydrofuran (47.9 mL), Lawesson'sReagent (4.26 g, 10.5 mmol) was added, and the resulting reactionmixture heated to 50° C. overnight. Upon completion, the reactionmixture concentrated and purified by silica gel chromatography (eluent:EtOAc/hexanes). Product containing fractions were combined and stirredwith 5g of 10% Palladium on carbon and filtered. The solution wasconcentrated and purified by silica gel chromatography (eluent:MeOH/DCM).

ES/MS: 520.2 [M+H]⁺

tert-butyl(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate:A microwave vial was charged with tert-butyl(4-(5-(6-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate(86.0 mg, 0.136 mmol), 27-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(1-8, 58.7 mg, 0.218 mmol), XPhos Pd G3 (8.63 mg, 0.010 mmol), 2Maqueous potassium phosphate tribasic (0.138 mL, 0.276 mmol). DMF (2.0mL) was added, and the reaction mixture was degassed by bubbling argonfor 60 seconds. The vial was sealed and heated with stirring at 120° C.for 30 minutes in a microwave reactor. The cooled reaction mixture wasdiluted with THF and filtered through a syringe filer, concentrated invacuo, and purified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yieldthe product as a trifluoroacetate salt.

ES/MS: 539.38 (M-41⁺)

7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 336): To a solution of tert-butyl(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate(24.8 mg, 0.039 mmol) in 0.04 mL 1,2-dichloroethane was added 4M HCl indioxane (0.0964 mL, 0.039 mmol). The solution was stirred for lh at rtduring which time a precipitate formed. The reaction mixture wasconcentrated in vacuo, and purified by RP-HPLC (eluent: water/MeCN*0.1%TFA) to yield the product Example 336 as a trifluoroacetate salt.

ES/MS: 527.33 (M+H⁺)

1H NMR (400 MHz, Acetonitrile-d3) δ 9.90 (s, 1H), 8.69 (d, J=2.1 Hz,1H), 8.65 (d, J=2.1 Hz, 1H), 8.57 (d, J=2.7 Hz, 1H), 8.54 (s, 1H), 8.07(d, J=5.1 Hz, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.55 (s, 1H), 7.23 (d, J=5.1Hz, 1H), 6.71 (dd, J=2.8, 1.7 Hz, 1H), 5.48 (s, 2H), 5.38 (t, J=4.9 Hz,1H), 4.32 (dq, J=13.1, 6.5 Hz, 1H), 2.30-2.25 (m, 1H), 2.23-2.16 (m,1H), 2.11 (s, 1H), 2.05 (q, J=6.7 Hz, 3H), 1.47 (d, J=6.4 Hz, 7H).

Procedure 40: Example 337:

N-(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)-2-hydroxy-2-methylpropanamide(Example 337)

N-(4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)-2-hydroxy-2-methylpropanamide(Example337): To a solution of crude7-(5-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-thiadiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (12.0 mg, 0.018 mmol) and 2-hydroxy-2-methyl-propanoicacid (23.7 mg, 0.227 mmol) in DMF (0.5 mL) was addedN,N-diisopropylethylamine (0.011 mL, 0.059 mmol) followed by theaddition of a solution of HATU (7.48 mg, 0.019 mmol) in DMF (0.1 mL).The reaction mixture was stirred at RT overnight then directly purifiedby RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product Example337 as a trifluoroacetate salt.

ES/MS: 613.40 [M+H]⁺

1H NMR (400 MHz, Acetonitrile-d3) δ 10.14 (d, J=7.7 Hz, 1H), 8.69 (s,1H), 8.65-8.60 (m, 2H), 8.11 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.21 (d,J=5.1 Hz, 1H), 6.71 (s, 1H), 4.24-4.14 (m, 1H), 4.01 (dt, J=12.0, 3.8Hz, 3H), 3.67 (ddd, J=12.0, 10.6, 2.4 Hz, 3H), 2.19 (dd, J=10.8, 4.4 Hz,6H), 2.10 (dd, J=10.6, 4.6 Hz, 6H), 1.32 (s, 6H).

Single isomers were isolated by chiral supercritical fluidchromatography separation.

The following compounds were made according to the previous procedures,using the appropriate starting materials and protecting group chemistryas needed:

ES/MS Pro- Structure # m/z Name cedure

338 660.85 N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((tetrahydro-2H- pyran-4- yl)amino)pyridin- 3-yl)-1,3,4- thiadiazol-2-yl)bicyclo[2.2.2] octan-1- yl)-2-((dimethyl (oxo)-l6- sulfanylidene)amino)acetamide 40

339 592.33 N-((1r,4r)-4-(5-(6- (3-cyanopyrrolo [1,2-b]pyridazin-7-yl)-4-(isopropyl- amino)pyridin- 3-yl)-1,3,4- thiadiazol-2-yl)cyclohexyl)-2- ((dimethyl(oxo)-l6- sulfanylidene) amino) acetamide 34

340 584.38 N-((1r,4r)-4-(5-(6- (3-cyanopyrrolo [1,2-b]pyridazin-7-yl)-4-(isopropyl- amino)pyridin-3- yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-1- methylpiperidine-4- carboxamide 34

341 573.21 3-(((1r,4r)-4-(5-(6- (3-cyanopyrrolo [1,2-b]pyridazin-7-yl)-4-(isopropyl- amino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)cyclohexyl) amino)-2,2- dimethyl-3- oxopropanoic acid 34

342 529.32 N-((1S,4r)-4-(5-(6- (3-cyanopyrrolo [1,2-b]pyridazin-7-yl)-4-(((S)- tetrahydrofuran-3- yl)amino)pyridin- 3-yl)-1,3,4-thiadiazol-2- yl)cyclohexyl) acetamide 34

343 652.4  N-(4-(5-(6-(3- cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((tetrahydro-2H- pyran-4-yl)amino) pyridin-3-yl)-1,3,4-thiadiazol-2-yl) bicyclo[2.2.2]octan- 1-yl)-1- methylpiperidine-4-carboxamide 40

1HNMR

Proton NMR data for each compound exemplified is shown in Table 1.

TABLE 1 Compound 1H-NMR 1 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J =2.2 Hz, 1H), 8.73 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 5.1Hz, 1H), 7.98 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.34 (p, J = 6.4 Hz,1H), 3.56 (t, J = 6.4 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H), 1.51 (d, J =6.4 Hz, 6H), 1.44 (s, 9H). 2 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J= 2.1 Hz, 1H), 8.73 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 5.1Hz, 1H), 8.02 (s, 1H), 7.38-6.97 (m, 2H), 4.21-4.05 (m, 1H), 3.85-3.68(m, 0H), 3.29-3.17 (m, 2H), 2.49-2.35 (m, 4H), 2.34-2.26 (m, 2H),2.14-2.06 (m, 2H), 2.06-1.96 (m, 2H), 1.94 (s, 3H), 1.90-1.68 (m, 4H),1.55-1.40 (m, 2H). 3 1H NMR (400 MHz, Methanol-d4) δ 8.82-8.70 (m, 3H),7.98 (d, J = 5.0 Hz, 1H), 7.76 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.05(d, J = 6.6 Hz, 2H), 3.83-3.70 (m, 1H), 2.42-2.08 (m, 4H), 2.00-1.93 (m,6H), 1.83 (dd, J = 12.5, 3.3 Hz, 2H), 1.51 (dd, J = 11.9, 3.4 Hz, 2H). 41H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J =2.2 Hz, 1H), 8.47 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.86 (s, 1H), 7.23(d, J = 5.1 Hz, 1H), 4.53 (s, 4H), 4.28 (p, J = 6.4 Hz, 1H), 3.68-3.61(m, 4H), 2.11-2.04 (m, 4H), 1.46 (d, J = 6.4 Hz, 6H). 5 1H NMR (400 MHz,Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.74 (s, 1H), 8.68 (d, J = 2.2Hz, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.99 (s, 1H), 7.23 (d, J = 5.0 Hz,1H), 5.05 (s, 2H), 4.30 (hept, J = 6.4 Hz, 1H), 1.49 (d, J = 6.4 Hz,6H). 6 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.68(d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.06 (d, J= 5.1 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (p, J = 6.4Hz, 1H), 4.09-3.90 (m, 3H), 3.52-3.39 (m, 2H), 2.05 (dd, J = 12.8, 3.9Hz, 2H), 1.96 (s, 3H), 1.75-1.54 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 7 1HNMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.1 Hz, 1H), 8.69 (dd, J =5.5, 2.0 Hz, 2H), 8.07 (d, J = 5.1 Hz, 1H), 7.98 (s, 1H), 7.75 (d, J =8.3 Hz, 2H), 7.24 (d, J = 4.9 Hz, 1H), 6.73 (d, J = 7.8 Hz, 2H), 4.31(dq, J = 12.7, 6.8, 6.3 Hz, 1H), 1.53 (d, J = 6.4 Hz, 6H). 8 1H NMR (400MHz, Methanol-d4) δ 8.84 (s, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.72 (d, J =2.2 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.27 (d, J = 5.0Hz, 1H), 5.00 (d, J = 14.2 Hz, 1H), 4.57 (d, J = 13.7 Hz, 1H), 4.36 (p,J = 6.4 Hz, 1H), 4.05 (dq, J = 10.2, 5.2, 4.1 Hz, 1H), 3.55 (t, J = 12.8Hz, 1H), 3.26-3.17 (m, 1H), 2.13-2.02 (m, 2H), 1.98 (s, 3H), 1.53 (d, J= 6.4 Hz, 8H). 9 1H NMR (400 MHz, Methanol-d4) δ 8.84 (s, 1H), 8.79 (d,J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H),8.02 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.35 (p, J = 6.5 Hz, 1H), 4.19(t, J = 6.8 Hz, 2H), 3.73 (t, J = 6.9 Hz, 2H), 2.12 (q, J = 6.6 Hz, 2H),2.04 (p, J = 6.5 Hz, 2H), 1.52 (d, J = 6.4 Hz, 6H). 10 1H NMR (400 MHz,Methanol-d4) δ 8.85 (d, J = 1.1 Hz, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.72(d, J = 2.1 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.26 (d, J= 5.0 Hz, 1H), 4.37 (ddt, J = 18.8, 12.0, 5.5 Hz, 3H), 3.92 (dd, J =6.5, 4.0 Hz, 1H), 3.86 (t, J = 5.5 Hz, 1H), 3.82-3.73 (m, 4H), 2.20 (d,J = 4.3 Hz, 3H), 1.52 (d, J = 6.4 Hz, 6H). 11 1H NMR (400 MHz,Methanol-d4) δ 8.88 (s, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2Hz, 1H), 8.11 (d, J = 5.0 Hz, 1H), 8.04 (s, 1H), 7.26 (d, J = 5.1 Hz,1H), 4.35 (hept, J = 6.4 Hz, 1H), 3.58 (t, J = 6.6 Hz, 4H), 3.27-3.19(m, 2H), 2.97 (td, J = 12.6, 3.1 Hz, 2H), 2.19-2.08 (m, 2H), 1.99 (d, J= 14.2 Hz, 2H), 1.81 (ddt, J = 18.6, 15.7, 10.0 Hz, 3H), 1.62-1.46 (m,7H). 12 1H NMR (400 MHz, Methanol-d4) δ 8.84 (d, J = 1.9 Hz, 1H), 8.79(d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.43 (d, J = 6.2 Hz, 0H),8.09 (d, J = 5.1 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 5.0 Hz,1H), 4.49 (dt, J = 12.3, 5.4 Hz, 1H), 4.36 (ddd, J = 29.8, 13.4, 6.7 Hz,3H), 4.13 (dd, J = 12.4, 4.5 Hz, 1H), 3.96 (dd, J = 13.0, 6.3 Hz, 1H),3.91-3.78 (m, 1H), 3.65 (dd, J = 13.1, 4.3 Hz, 1H), 2.32 (ddd, J = 30.8,13.3, 6.2 Hz, 1H), 2.16-2.00 (m, 1H), 1.99 (d, J = 3.6 Hz, 3H), 1.52(dd, J = 6.4, 1.3 Hz, 6H). 13 1H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J= 2.0 Hz, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.10(d, J = 5.1 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H),4.55-4.44 (m, 1H), 4.43-4.28 (m, 3H), 4.13 (dd, J = 12.4, 4.5 Hz, 1H),3.96 (dd, J = 13.1, 6.3 Hz, 1H), 3.90-3.77 (m, 1H), 3.65 (dd, J = 13.0,4.3 Hz, 0H), 2.41-2.23 (m, 1H), 2.18-2.00 (m, 1H), 1.99 (d, J = 3.6 Hz,3H), 1.52 (dd, J = 6.4, 1.4 Hz, 6H). 14 1H NMR (400 MHz, Methanol-d4) δ9.35 (t, J = 5.9 Hz, 1H), 8.84 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.71(d, J = 2.1 Hz, 1H), 8.09 (d, J = 5.1 Hz, 1H), 8.04 (s, 1H), 7.25 (d, J= 5.1 Hz, 1H), 4.48 (ddd, J = 48.7, 9.0, 2.4 Hz, 1H), 4.33 (h, J = 6.3Hz, 1H), 4.01-3.84 (m, 1H), 3.77-3.62 (m, 1H), 1.52 (d, J = 6.4 Hz, 6H),1.32 (d, J = 1.5 Hz, 6H). 15 1H NMR (400 MHz, Methanol-d4) δ 8.84 (s,1H), 8.79 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.10 (d, J =5.0 Hz, 1H), 8.02 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.35 (dt, J = 12.9,6.0 Hz, 1H), 3.05-3.01 (m, 3H), 1.52 (d, J = 6.4 Hz, 6H). 16 1H NMR (400MHz, Methanol-d4) δ 8.85 (s, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.72 (d, J =2.2 Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.26 (d, J = 5.1Hz, 1H), 4.61 (q, J = 3.0, 2.1 Hz, 0H), 4.54 (t, J = 3.4 Hz, 1H),4.46-4.11 (m, 3H), 3.86 (dt, J = 10.2, 5.1 Hz, 1H), 3.77 (d, J = 2.9 Hz,1H), 2.27-2.00 (m, 2H), 1.53 (d, J = 6.4 Hz, 6H). 17 1H NMR (400 MHz,Methanol-d4) δ 8.85 (s, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.10 (d, J = 5.0 Hz, 1H), 8.02 (s, 1H), 7.26 (d, J = 5.0 Hz,1H), 4.63-4.58 (m, 0H), 4.54 (t, J = 3.3 Hz, 1H), 4.45-4.12 (m, 3H),3.86 (dt, J = 10.1, 5.1 Hz, 1H), 3.77 (d, J = 2.8 Hz, 1H), 2.26-2.00 (m,2H), 1.53 (d, J = 6.4 Hz, 6H). 18 1H NMR (400 MHz, DMS0-d6) δ 9.48 (s,1H), 8.99 (d, J = 2.2 Hz, 1H), 8.91 (s, 1H), 8.86 (d, J = 2.2 Hz, 1H),8.12 (s, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.24 (d, J = 5.0 Hz, 1H),4.33-4.13 (m, 6H), 1.40 (d, J = 6.3 Hz, 6H). 19 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.72 (s, 1H), 8.71 (d, J = 2.2Hz, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.25 (d, J = 5.1 Hz,1H), 4.39-4.27 (m, 1H), 2.34 (s, 3H), 1.52-1.47 (m, 6H). 20 1H NMR (400MHz, Methanol-d4) δ 8.84 (s, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.70 (s,1H), 8.24 (s, 1H), 8.13 (d, J = 5.0 Hz, 1H), 7.25 (d, J = 5.0 Hz, 1H),3.84-3.70 (m, 2H), 2.34 (d, J = 13.3 Hz, 2H), 2.12 (d, J = 13.0 Hz, 2H),1.97 (s, 3H), 1.91-1.69 (m, 2H), 1.50 (d, J = 12.4 Hz, 2H). 21 1H NMR(400 MHz, Methanol-d4) δ 8.82-8.77 (m, 2H), 8.73 (d, J = 2.1 Hz, 1H),8.08 (d, J = 5.1 Hz, 1H), 7.76 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H),5.33-5.17 (m, 3H), 4.82 (dd, J = 6.7, 5.4 Hz, 2H), 3.87-3.73 (m, 1H),2.35 (d, J = 13.1 Hz, 2H), 2.12 (d, J = 12.8 Hz, 2H), 1.97 (s, 3H),1.91-1.76 (m, 2H), 1.60-1.42 (m, 2H). 22 1H NMR (400 MHz, Methanol-d4) δ8.76 (s, 1H), 8.68 (s, 2H), 8.08 (d, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.23(s, 1H), 3.81-3.68 (m, 1H), 2.19 (dd, J = 84.7, 13.0 Hz, 4H), 2.03 (d, J= 1.8 Hz, 1H), 1.94 (d, J = 1.9 Hz, 3H), 1.79 (q, J = 12.9 Hz, 2H), 1.47(q, J = 12.6 Hz, 2H), 1.33 (d, J = 37.6 Hz, 1H), 0.94-0.80 (m, 1H). 231H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 7.3 Hz, 2H), 8.70 (s, 1H),8.03 (d, J = 5.3 Hz, 1H), 7.91 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H),4.60-4.54 (m, 1H), 3.74 (s, 2H), 3.68 (s, 3H), 3.37 (d, J = 7.3 Hz, 2H),2.54 (s, 4H), 2.31 (d, J = 13.8 Hz, 5H), 2.09 (d, J = 12.8 Hz, 3H), 1.94(s, 3H), 1.85-1.70 (m, 2H), 1.58-1.40 (m, 1H), 1.28 (s, 2H), 0.89 (s,1H). 24 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.74(s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.97 (s,1H), 7.26 (d, J = 5.1 Hz, 1H), 4.42-4.28 (m, 1H), 3.89-3.67 (m, 2H),2.34 (d, J = 13.5 Hz, 2H), 2.12 (d, J = 12.7 Hz, 2H), 1.97 (s, 3H), 1.82(q, J = 13.3, 12.7 Hz, 2H), 1.61-1.42 (m, 8H). 25 1H NMR (400 MHz,Methanol-d4) δ 8.63-8.55 (m, 1H), 8.52 (s, 1H), 8.32 (d, J = 2.9 Hz,1H), 7.84 (t, J = 4.5 Hz, 1H), 7.10 (t, J = 5.0 Hz, 1H), 5.48 (s, 0H),5.34 (s, 1H), 4.04 (s, 0H), 2.82 (d, J = 3.7 Hz, 1H), 2.18 (s, 1H),2.08-1.97 (m, 2H), 1.60 (s, 1H), 1.46-1.40 (m, 3H), 1.31 (d, J = 15.4Hz, 13H), 0.95-0.82 (m, 2H). 26 1H NMR (400 MHz, Methanol-d4) δ8.82-8.63 (m, 3H), 8.07 (d, J = 5.3 Hz, 2H), 7.24 (d, J = 5.0 Hz, 1H),4.31 (p, J = 6.4 Hz, 1H), 3.66-3.55 (m, 4H), 1.50 (d, J = 6.4 Hz, 6H).27 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.67 (d, J= 2.2 Hz, 1H), 8.43 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H),7.23 (d, J = 5.1 Hz, 1H), 4.68-4.40 (m, 1H), 4.28 (p, J = 6.5 Hz, 1H),4.07-3.85 (m, 1H), 3.63 (td, J = 15.0, 9.6 Hz, 1H), 1.47 (d, J = 6.4 Hz,6H), 1.29 (d, J = 1.5 Hz, 6H). 28 1H NMR (400 MHz, Methanol-d4) δ 8.78(d, J = 2.2 Hz, 1H), 8.70 (d, J = 1.9 Hz, 2H), 8.09 (d, J = 5.0 Hz, 1H),7.96 (s, 1H), 7.56-7.45 (m, 2H), 7.25 (d, J = 5.0 Hz, 1H), 6.48 (t, J =2.2 Hz, 2H), 4.34 (p, J = 6.4 Hz, 1H), 1.50 (d, J = 6.4 Hz, 6H). 29 1HNMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2Hz, 1H), 8.49 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d,J = 5.1 Hz, 1H), 4.37-4.24 (m, 1H), 3.67-3.60 (m, 4H), 2.22-2.15 (m,4H), 1.53-1.43 (m, 6H). 30 1H NMR (400 MHz, Methanol-d4) δ 9.62 (s, 1H),8.83 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.10(d, J = 5.0 Hz, 1H), 8.02 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.35 (hept,J = 6.3 Hz, 1H), 1.53 (d, J = 6.4 Hz, 6H). 31 1H NMR (400 MHz,Methanol-d4) δ 8.80 (d, J = 2.2 Hz, 1H), 8.74-8.71 (m, 2H), 8.11 (d, J =5.1 Hz, 1H), 7.97 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.35 (hept, J = 6.4Hz, 1H), 3.41-3.35 (m, 2H), 2.12-1.99 (m, 2H), 1.52 (d, J = 6.4 Hz, 6H),1.33 (s, 6H). 32 1H NMR (400 MHz, Methanol-d4) d 8.77 (d, J = 2.1 Hz,1H), 8.73 (s, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H),7.96 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 4.32 (p, J = 6.4 Hz, 1H),4.13-4.03 (m, 2H), 3.68-3.54 (m, 3H), 2.19-2.11 (m, 2H), 2.07-1.92 (m,2H), 1.49 (d, J = 6.4 Hz, 6H). 33 1H NMR (400 MHz, Methanol-d4) δ 8.76(d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J= 5.1 Hz, 1H), 7.88 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.54 (t, J = 8.3Hz, 2H), 4.29 (p, J = 6.5 Hz, 1H), 4.17 (dd, J = 8.8, 5.4 Hz, 2H), 2.00(s, 3H), 1.46 (d, J = 6.4 Hz, 6H), 1.39-1.28 (m, 1H). 34 1H NMR (400MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.72 (s, 1H), 8.68 (d, J =2.1 Hz, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.98 (s, 1H), 7.24 (d, J = 5.0Hz, 1H), 4.08-3.94 (m, 1H), 3.84-3.70 (m, 1H), 3.65 (s, 3H), 3.58-3.44(m, 1H), 3.31-3.23 (m, 1H), 2.39-2.22 (m, 4H), 2.19-2.04 (m, 4H), 1.95(s, 3H), 1.90-1.73 (m, 2H), 1.73-1.40 (m, 6H). 35 1H NMR (400 MHz,Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.52(s, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.23 (d, J = 5.1 Hz,1H), 4.30 (hept, J = 6.2 Hz, 1H), 4.23-3.99 (m, 4H), 3.91-3.79 (m, 1H),3.74-3.61 (m, 1H), 3.61-3.51 (m, 1H), 3.46-3.37 (m, 1H), 3.20-3.07 (m,1H), 3.07-2.93 (m, 1H), 1.47 (d, J = 6.4 Hz, 6H). - 3 protons hiddenbelow pentet of deuterated methanol at 3.31 ppm 36 1H NMR (400 MHz,Methanol-d4) δ 8.77 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.52(s, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.23 (d, J = 5.1 Hz,1H), 4.40-4.23 (m, 1H), 4.22-4.14 (m, 1H), 4.14-4.08 (m, 1H), 4.07-3.98(m, 2H), 3.90-3.78 (m, 1H), 3.72-3.60 (m, 1H), 3.59-3.49 (m, 1H),3.43-3.36 (m, 1H), 3.31-3.17 (m, 3H), 3.13-3.03 (m, 1H), 3.03-2.94 (m,1H), 1.47 (d, J = 6.4 Hz, 6H). 37 1H NMR (400 MHz, Methanol-d4) δ 8.75(d, J = 2.2 Hz, 1H), 8.68-8.64 (m, 2H), 8.58 (s, 1H), 8.04 (d, J = 5.0Hz, 1H), 7.78 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 4.27-4.13 (m, 3H), 1.35(d, J = 6.4 Hz, 6H), 1.28 (s, 6H). 38 1H NMR (400 MHz, Methanol-d4) δ8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06(d, J = 5.0 Hz, 1H), 8.00 (d, J = 5.7 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J= 5.0 Hz, 1H), 4.29 (p, J = 6.4 Hz, 1H), 4.01-3.94 (m, 1H), 3.80 (dd, J= 12.4, 3.1 Hz, 2H), 3.54 (d, J = 11.9 Hz, 2H), 2.43 (s, 2H), 2.08-1.99(m, 2H), 1.98 (s, 3H), 1.73-1.62 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 391H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J =2.2 Hz, 1H), 8.49 (s, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.23(d, J = 5.0 Hz, 1H), 4.29 (p, J = 6.4 Hz, 1H), 3.98 (t, J = 4.8 Hz, 1H),3.71-3.56 (m, 4H), 2.46 (s, 2H), 2.04 (s, 3H), 2.02-1.93 (m, 2H),1.77-1.63 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 40 1H NMR (400 MHz,Methanol-d4) δ 8.82 (d, J = 5.6 Hz, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.71(d, J = 2.2 Hz, 1H), 8.38 (s, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.96 (d, J= 2.7 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.46 (d, J = 6.0 Hz, 1H),4.40-4.28 (m, 1H), 4.24 (dd, J = 11.2, 6.0 Hz, 1H), 4.09-4.01 (m, 1H),3.99-3.93 (m, 0H), 3.91-3.76 (m, 2H), 3.62 (dd, J = 12.8, 4.7 Hz, 0H),2.29 (dq, J = 13.6, 6.8 Hz, 1H), 2.13-1.99 (m, 1H), 1.98 (d, J = 19.5Hz, 3H), 1.53-1.47 (m, 6H). 41 1H NMR (400 MHz, Methanol-d4) δ 8.83 (d,J = 1.1 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H),8.09 (d, J = 5.1 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.24 (d, J = 5.1 Hz,1H), 4.46 (s, 1H), 4.39-4.29 (m, 1H), 4.27-4.10 (m, 1H), 3.86-3.57 (m,2H), 3.47 (dd, J = 13.6, 4.6 Hz, 1H), 2.27-2.01 (m, 4H), 1.99-1.85 (m,3H), 1.56-1.43 (m, 6H). 42 1H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J =1.1 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.09(d, J = 5.0 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 7.24 (d, J = 5.0 Hz, 1H),4.55-4.40 (m, 1H), 4.40-4.29 (m, 1H), 4.28-4.10 (m, 1H), 3.85-3.66 (m,1H), 3.66-3.57 (m, 1H), 3.52-3.43 (m, 1H), 2.23-2.00 (m, 4H), 1.98-1.83(m, 3H), 1.51 (dd, J = 6.5, 1.8 Hz, 6H). 43 1H NMR (400 MHz,Methanol-d4) δ 8.83 (d, J = 1.3 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.70(d, J = 2.2 Hz, 1H), 8.09 (d, J = 5.1 Hz, 1H), 8.00 (s, 1H), 7.24 (d, J= 5.1 Hz, 1H), 4.42-4.22 (m, 4H), 4.14-3.88 (m, 1H), 3.87-3.74 (m, 1H),3.69-3.60 (m, 3H), 2.40-2.19 (m, 1H), 2.16-1.96 (m, 1H), 1.51 (d, J =6.4 Hz, 6H). 44 1H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J = 1.3 Hz,1H), 8.77 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.09 (d, J =5.1 Hz, 1H), 8.00 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 4.43-4.23 (m, 4H),4.18-3.88 (m, 1H), 3.86-3.74 (m, 1H), 3.72-3.58 (m, 3H), 2.43-2.18 (m,1H), 2.17-1.95 (m, 1H), 1.51 (d, J = 6.4 Hz, 6H). 45 1H NMR (400 MHz,Methanol-d4) δ 8.77 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.54(s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.88 (s, 1H), 7.23 (d, J = 5.0 Hz,1H), 4.37-4.23 (m, 2H), 3.88-3.66 (m, 4H), 2.87-2.78 (m, 2H), 2.15 (dt,J = 10.9, 5.9 Hz, 1H), 1.96 (s, 3H), 1.61 (d, J = 10.2 Hz, 1H), 1.48 (d,J = 6.4 Hz, 6H). 46 1H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J = 2.7 Hz,1H), 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.09 (d, J =5.1 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.49(dt, J = 11.8, 5.8 Hz, 1H), 4.43- 4.24 (m, 3H), 4.03 (ddd, J = 67.1,12.7, 5.4 Hz, 1H), 3.83 (qd, J = 13.0, 6.2 Hz, 1H), 3.64 (dd, J = 13.0,4.3 Hz, 0.5H), 3.21 (q, J = 7.4 Hz, 0.5H), 2.30 (ddt, J = 27.5, 13.6,6.5 Hz, 1H), 2.07 (ddt, J = 31.9, 12.7, 6.1 Hz, 1H), 1.60 (tq, J = 8.3,4.6, 3.7 Hz, 1H), 1.51 (dd, J = 6.4, 1.7 Hz, 6H), 1.31 (t, J = 7.3 Hz,0.5H), 1.07 (d, J = 6.7 Hz, 1H), 0.87 (td, J = 4.6, 2.6 Hz, 2H),0.82-0.70 (m, 2H). 47 1H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J = 2.7Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.09 (d, J= 5.1 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H),4.55-4.43 (m, 1H), 4.42-4.26 (m, 3H), 4.16-3.59 (m, 3H), 2.45-2.20 (m,1H), 2.20-1.99 (m, 1H), 1.83-1.55 (m, 1H), 1.51 (dd, J = 6.4, 1.7 Hz,6H), 1.10-1.04 (m, 1H), 0.93-0.83 (m, 2H), 0.82-0.73 (m, 2H). 48 1H NMR(400 MHz, Methanol-d4) δ 8.82 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 2.2 Hz,1H), 8.70 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 5.1 Hz, 1H), 8.00 (d, J =2.0 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.70-4.46 (m, 1H), 4.43-3.86 (m,3H), 3.82-3.64 (m, 1H), 3.62-3.51 (m, 0.5H), 3.21 (dd, J = 12.7, 8.9 Hz,0.5H), 2.17-1.89 (m, 5H), 1.85-1.60 (m, 2H), 1.51 (d, J = 6.4 Hz, 6H).49 1H NMR (400 MHz, Methanol-d4) δ 8.82 (d, J = 2.3 Hz, 1H), 8.78 (d, J= 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 5.0 Hz, 1H), 8.00(d, J = 1.9 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.71-4.44 (m, 1H),4.41-3.85 (m, 3H), 3.83-3.65 (m, 1H), 3.61-3.51 (m, 0H), 3.21 (dd, J =12.6, 9.0 Hz, 0H), 2.12-1.90 (m, 5H), 1.83-1.61 (m, 2H), 1.51 (d, J =6.4 Hz, 6H). 50 1H NMR (400 MHz, Methanol-d4) δ 9.06 (s, 1H), 8.73 (s,1H), 7.74 (d, J = 5.2 Hz, 1H), 7.71 (s, 1H), 7.08 (d, J = 5.1 Hz, 1H),4.65-4.57 (m, 1H), 4.33 (p, J = 6.4 Hz, 1H), 3.84-3.68 (m, 1H),3.63-3.52 (m, 1H), 2.31 (d, J = 13.0 Hz, 2H), 2.10 (d, J = 12.8 Hz, 2H),2.06-1.65 (m, 13H), 1.67-1.36 (m, 9H). 51 1H NMR (400 MHz, Methanol-d4)δ 8.76 (s, 2H), 8.51 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.83 (s, 1H),7.23 (d, J = 5.1 Hz, 1H), 4.56 (t, J = 7.4 Hz, 1H), 4.20-3.95 (m, 4H),3.81 (t, J = 11.7 Hz, 1H), 3.69 (s, 3H), 3.69-3.57 (m, 1H), 3.55-3.45(m, 1H), 3.37 (d, J = 7.4 Hz, 2H), 3.27-3.01 (m, 4H), 3.02-2.76 (m, 2H),2.68-2.44 (m, 3H), 2.38-2.21 (m, 2H). 52 1H NMR (400 MHz, Methanol-d4) δ8.76 (s, 2H), 8.48 (s, 1H), 8.04 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 5.7Hz, 1H), 7.80 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.68-4.49 (m, 1H),4.03-3.95 (m, 1H), 3.87-3.76 (m, 2H), 3.69 (s, 3H), 3.54 (d, J = 11.9Hz, 2H), 3.43-3.34 (m, 2H), 2.72-2.48 (m, 3H), 2.44 (s, 2H), 2.37-2.22(m, 2H), 2.15-1.99 (m, 2H), 1.98 (s, 3H), 1.76-1.61 (m, 2H). 53 1H NMR(400 MHz, Methanol-d4) δ 8.80 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.1 Hz,1H), 8.64 (s, 1H), 8.14 (d, J = 5.1 Hz, 1H), 8.08 (s, 1H), 8.03 (d, J =5.8 Hz, 1H), 7.27 (d, J = 5.0 Hz, 1H), 5.26 (q, J = 6.9 Hz, 1H), 4.01(d, J = 4.9 Hz, 1H), 3.84 (d, J = 12.0 Hz, 2H), 3.57 (d, J = 11.9 Hz,2H), 2.46 (s, 2H), 2.08-1.98 (m, 5H), 1.92 (d, J = 7.0 Hz, 3H),1.75-1.64 (m, 2H). 54 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.07 (d, J = 5.0 Hz,1H), 8.00 (d, J = 5.8 Hz, 1H), 7.88 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H),4.05-3.91 (m, 2H), 3.80 (dd, J = 12.3, 3.1 Hz, 2H), 3.64 (s, 3H), 3.54(d, J = 11.8 Hz, 3H), 2.43 (s, 2H), 2.33-2.22 (m, 2H), 2.13-1.97 (m,4H), 1.98 (s, 3H), 1.76-1.49 (m, 6H). 55 1H NMR (400 MHz, Methanol-d4) δ8.77 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 8.07(d, J = 5.0 Hz, 1H), 7.88 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.41 (s,3H), 4.36-4.23 (m, 1H), 2.32-2.18 (m, 2H), 2.13-2.02 (m, 2H), 2.02-1.92(m, 2H), 1.88 (s, 3H), 1.86-1.73 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 561H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J =2.2 Hz, 1H), 8.48 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 8.03 (d, J = 5.3Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.35 (s, 2H), 4.33-4.20(m, 1H), 3.99-3.88 (m, 1H), 2.48-2.34 (m, 2H), 2.28-2.20 (m, 4H), 1.99(s, 3H), 1.91 (d, J = 15.1 Hz, 2H), 1.47 (d, J = 6.4 Hz, 6H). 57 1H NMR(400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz,1H), 8.48 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J =5.1 Hz, 1H), 4.38-4.18 (m, 1H), 3.87 (s, 1H), 3.80 (dd, J = 12.3, 3.1Hz, 2H), 3.66 (t, J = 4.8 Hz, 4H), 3.60-3.50 (m, 2H), 3.39 (t, J = 4.8Hz, 4H), 2.49 (s, 2H), 2.09-1.97 (m, 2H), 1.72-1.59 (m, 2H), 1.47 (d, J= 6.4 Hz, 6H). 58 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz,1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H),7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (p, J = 6.5 Hz, 1H), 3.81(dd, J = 12.5, 3.2 Hz, 2H), 3.73 (s, 1H), 3.55 (s, 1H), 3.52 (s, 1H),3.04 (s, 3H), 2.52 (s, 2H), 2.13-1.99 (m, 2H), 1.74-1.62 (m, 2H), 1.47(d, J = 6.4 Hz, 6H). 59 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.0 Hz,1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.37-4.22 (m, 1H),3.83-3.63 (m, 6H), 3.56-3.42 (m, 2H), 2.48-2.35 (m, 2H), 2.10-1.89 (m,2H), 1.71-1.57 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 60 1H NMR (400 MHz,Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.50(s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.23 (d, J = 5.0 Hz,1H), 4.43-4.21 (m, 1H), 3.90 (dd, J = 12.6, 3.2 Hz, 2H), 3.65 (s, 1H),3.55 (s, 1H), 3.52 (s, 1H), 2.59 (s, 2H), 2.12-1.99 (m, 2H), 1.93-1.79(m, 2H), 1.46 (d, J = 6.4 Hz, 6H). 61 1H NMR (400 MHz, Methanol-d4) δ9.07 (s, 1H), 8.65 (s, 1H), 8.02 (d, J = 5.8 Hz, 1H), 7.97 (s, 1H), 7.70(d, J = 5.1 Hz, 1H), 7.09 (d, J = 5.1 Hz, 1H), 5.22 (q, J = 6.9 Hz, 1H),4.64 (d, J = 4.1 Hz, 1H), 4.07-3.95 (m, 1H), 3.81 (d, J = 11.9 Hz, 2H),3.55 (d, J = 11.6 Hz, 3H), 2.44 (s, 2H), 2.06-1.93 (m, 6H), 1.93-1.72(m, 8H), 1.75-1.63 (m, 4H), 1.62-1.49 (m, 1H). 62 1H NMR (400 MHz,Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.45(s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.87 (s,1H), 7.23 (d, J = 5.1 Hz, 1H), 4.28 (p, J = 6.3 Hz, 1H), 4.14 (d, J =13.2 Hz, 1H), 4.01 (d, J = 27.3 Hz, 3H), 3.59 (d, J = 12.4 Hz, 1H),3.46-3.37 (m, 1H), 2.21-2.06 (m, 1H), 1.99 (s, 3H), 1.74 (d, J = 12.6Hz, 1H), 1.47 (d, J = 6.4 Hz, 6H). 63 1H NMR (400 MHz, Methanol-d4) δ8.76 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.45 (s, 1H), 8.06(d, J = 5.1 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J= 5.0 Hz, 1H), 4.28 (p, J = 6.4 Hz, 1H), 4.21-4.11 (m, 1H), 4.09-3.93(m, 3H), 3.59 (d, J = 13.7 Hz, 1H), 3.41 (td, J = 12.8, 3.1 Hz, 1H),2.17-2.05 (m, 1H), 1.99 (s, 3H), 1.79-1.67 (m, 1H), 1.47 (d, J = 6.4 Hz,6H). 64 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68(d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.88 (s,1H), 7.23 (d, J = 5.1 Hz, 1H), 4.28 (p, J = 6.4 Hz, 1H), 4.14 (dd, J =12.8, 4.6 Hz, 1H), 3.99-3.82 (m, 2H), 3.65 (td, J = 9.1, 4.6 Hz, 1H),3.57-3.41 (m, 1H), 3.25 (dd, J = 13.0, 9.4 Hz, 1H), 2.21-2.06 (m, 1H),2.00 (s, 3H), 1.72-1.57 (m, 1H), 1.47 (d, J = 6.4 Hz, 6H). 65 1H NMR(400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz,1H), 8.48 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J =5.1 Hz, 1H), 4.29 (p, J = 6.4 Hz, 1H), 4.14 (dd, J = 13.0, 4.6 Hz, 1H),4.01-3.82 (m, 2H), 3.65 (td, J = 9.1, 4.6 Hz, 1H), 3.53-3.43 (m, 1H),3.25 (dd, J = 13.0, 9.4 Hz, 1H), 2.20-2.06 (m, 1H), 2.00 (s, 3H),1.72-1.57 (m, 1H), 1.47 (d, J = 6.4 Hz, 6H). 66 1H NMR (400 MHz,Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.46(s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.23 (d,J = 5.0 Hz, 1H), 4.29 (hept, J = 6.4, 6.0 Hz, 1H), 4.07 (s, 1H), 3.90(s, 2H), 2.32-2.20 (m, 2H), 2.19-2.09 (m, 2H), 1.94 (s, 7H), 1.47 (d, J= 6.4 Hz, 6H). 67 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz,1H), 8.68 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H),7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (hept, J = 6.1 Hz, 1H),4.06 (s, 4H), 3.66-3.51 (m, 4H), 2.13 (s, 3H), 2.01-1.83 (m, 4H), 1.46(d, J = 6.4 Hz, 6H). 68 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.0 Hz,1H), 7.88 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.46 (s, 2H), 4.43 (s, 4H),4.28 (p, J = 6.5 Hz, 1H), 4.22 (s, 2H), 1.88 (s, 3H), 1.46 (d, J = 6.4Hz, 6H). 69 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H),8.68 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.87(s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.28 (hept, J = 6.0, 5.6 Hz, 1H),4.01 (s, 2H), 3.93 (s, 2H), 3.73-3.60 (m, 1H), 2.12-2.04 (m, 2H), 1.93(s, 3H), 1.92-1.82 (m, 2H), 1.72 (td, J = 13.0, 3.6 Hz, 2H), 1.46 (d, J= 6.4 Hz, 6H), 1.40-1.25 (m, 2H). 70 1H NMR (400 MHz, Methanol-d4) δ8.77 (d, J = 1.9 Hz, 2H), 8.72 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 5.1 Hz,1H), 7.71 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 5.32-5.22 (m, 1H),5.23-5.15 (m, 2H), 4.80 (dd, J = 6.8, 5.4 Hz, 2H), 2.25-2.17 (m, 6H),2.18-2.08 (m, 6H), 1.90 (s, 3H). 71 1H NMR (400 MHz, Methanol-d4) δ 8.78(d, J = 2.1 Hz, 1H), 8.75 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.12 (d, J= 5.1 Hz, 1H), 7.99 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 4.31 (dt, J =9.8, 5.3 Hz, 1H), 4.10-3.98 (m, 2H), 3.79-3.66 (m, 2H), 2.28-2.16 (m,6H), 2.16-2.05 (m, 8H), 1.90 (s, 3H), 1.87-1.74 (m, 2H). 72 1H NMR (400MHz, Methanol-d4) δ 8.84 (s, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.71 (d, J =2.1 Hz, 1H), 8.16 (s, 1H), 8.13 (d, J = 5.1 Hz, 1H), 7.25 (d, J = 5.1Hz, 1H), 5.25 (q, J = 6.9 Hz, 1H), 2.27-2.16 (m, 6H), 2.17-2.08 (m, 6H),1.92 (d, J = 7.0 Hz, 3H), 1.90 (s, 3H). 73 1H NMR (400 MHz, Methanol-d4)δ 8.77 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.07(d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.41-4.24(m, 3H), 3.63-3.52 (m, 2H), 3.03 (s, 1H), 2.30 (ddd, J = 13.7, 11.1, 2.8Hz, 1H), 2.04 (d, J = 10.5 Hz, 1H), 1.95 (s, 3H), 1.90 (d, J = 10.5 Hz,1H), 1.60 (dt, J = 13.5, 3.8 Hz, 1H), 1.47 (d, J = 6.4 Hz, 6H). 74 1HNMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1Hz, 1H), 8.48 (s, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.23 (d,J = 5.0 Hz, 1H), 4.37-4.21 (m, 3H), 3.62-3.50 (m, 2H), 3.03 (s, 1H),2.30 (ddd, J = 13.7, 11.1, 2.8 Hz, 1H), 2.04 (d, J = 10.6 Hz, 1H), 1.95(s, 3H), 1.90 (d, J = 10.4 Hz, 1H), 1.60 (dt, J = 13.6, 3.9 Hz, 1H),1.47 (d, J = 6.4 Hz, 6H). 75 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J= 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.06 (d, J = 5.1Hz, 1H), 7.63 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 5.32-5.10 (m, 3H), 4.77(dd, J = 6.6, 5.1 Hz, 2H), 4.08 (s, 4H), 3.58 (dt, J = 22.0, 5.7 Hz,4H), 2.13 (s, 3H), 2.01-1.84 (m, 4H). 76 1H NMR (400 MHz, Methanol-d4) δ8.77 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.52 (s, 1H), 8.11(d, J = 5.1 Hz, 1H), 7.92 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.29 (dt, J= 9.7, 5.3 Hz, 1H), 4.07 (s, 4H), 4.06-3.98 (m, 2H), 3.78-3.67 (m, 2H),3.57 (dt, J = 22.1, 5.7 Hz, 4H), 2.25-2.15 (m, 2H), 2.13 (s, 3H),2.00-1.94 (m, 2H), 1.92-1.86 (m, 2H), 1.85-1.71 (m, 2H) 77 1H NMR (400MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H),8.60 (s, 1H), 8.16-8.04 (m, 2H), 7.24 (d, J = 5.1 Hz, 1H), 5.21 (q, J =7.0 Hz, 1H), 4.02 (s, 2H), 3.94 (s, 2H), 3.73-3.61 (m, 1H), 2.17-2.04(m, 2H), 1.93 (s, 3H), 1.92-1.81 (m, 5H), 1.77-1.67 (m, 2H), 1.40-1.25(m, 3H). 78 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.1 Hz, 1H),8.70 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.63(s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 5.31-5.12 (m, 3H), 4.77 (dd, J = 6.6,5.1 Hz, 2H), 4.03 (s, 2H), 3.95 (s, 2H), 3.74-3.60 (m, 1H), 2.09 (d, J =13.5 Hz, 2H), 1.93 (s, 3H), 1.91-1.81 (m, 2H), 1.80-1.66 (m, 2H), 1.33(q, J = 11.4, 10.9 Hz, 2H). 79 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d,J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.51 (s, 1H), 8.11 (d, J =5.0 Hz, 1H), 7.91 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.35-4.23 (m, 1H),4.07-3.98 (m, 4H), 3.94 (s, 2H), 3.78-3.61 (m, 3H), 2.18 (d, J = 13.1Hz, 2H), 2.08 (d, J = 13.4 Hz, 2H), 1.93 (s, 3H), 1.93-1.83 (m, 2H),1.83-1.66 (m, 4H), 1.42-1.24 (m, 2H). 80 1H NMR (400 MHz, Methanol-d4) δ8.78 (d, J = 2.2 Hz, 1H), 8.74 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.09(d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.32 (hept,J = 6.3 Hz, 1H), 1.73 (s, 6H), 1.49 (d, J = 6.4 Hz, 6H). 81 1H NMR (400MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.76 (s, 1H), 8.69 (d, J =2.2 Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.96 (s, 1H), 7.24 (d, J = 5.1Hz, 1H), 4.95 (dd, J = 11.1, 2.6 Hz, 1H), 4.32 (hept, J = 6.5 Hz, 1H),4.17 (ddd, J = 10.9, 4.8, 2.0 Hz, 1H), 4.03-3.87 (m, 1H), 3.38 (t, J =10.7 Hz, 1H), 2.52-2.38 (m, 1H), 2.25-2.13 (m, 1H), 1.96 (s, 3H),1.94-1.81 (m, 1H), 1.74 (qd, J = 12.4, 3.7 Hz, 1H), 1.49 (d, J = 6.4 Hz,6H). 82 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68(d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.87 (s,1H), 7.23 (d, J = 5.1 Hz, 1H), 4.28 (p, J = 6.4 Hz, 1H), 3.96 (d, J =14.7 Hz, 4H), 2.06-1.90 (m, 2H), 1.87-1.75 (m, 2H), 1.67-1.58 (m, 2H),1.57-1.48 (m, 2H), 1.46 (d, J = 6.4 Hz, 6H), 1.22 (s, 3H). 83 1H NMR(400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.74 (s, 1H), 8.69(d, J = 2.1 Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.23 (d, J= 5.0 Hz, 1H), 4.40-4.20 (m, 3H), 2.59-2.24 (m, 6H), 2.15-2.05 (m, 2H),1.91 (s, 3H), 1.48 (d, J = 6.4 Hz, 6H). 84 1H NMR (400 MHz, Methanol-d4)δ 8.77 (d, J = 2.2 Hz, 1H), 8.75 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.08(d, J = 5.1 Hz, 1H), 7.97 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 5.05 (dd, J= 9.7, 3.1 Hz, 1H), 4.32 (p, J = 6.4 Hz, 1H), 4.06-3.99 (m, 1H),3.99-3.89 (m, 2H), 2.31-2.01 (m, 4H), 2.00 (s, 3H), 1.49 (d, J = 6.4 Hz,6H). 85 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68(d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.87 (s,1H), 7.41 (d, J = 6.3 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.29 (p, J =6.4 Hz, 1H), 3.98 (d, J = 6.1 Hz, 1H), 3.83 (dd, J = 12.4, 3.1 Hz, 2H),3.56 (d, J = 11.9 Hz, 2H), 2.49 (s, 2H), 2.03-1.87 (m, 2H), 1.79-1.66(m, 2H), 1.47 (d, J = 6.4 Hz, 6H), 1.38 (s, 6H). 86 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.63(s, 1H), 8.12 (d, J = 5.1 Hz, 1H), 8.07 (s, 1H), 7.42 (d, J = 6.2 Hz,1H), 7.25 (d, J = 5.1 Hz, 1H), 5.24 (q, J = 7.0 Hz, 1H), 3.99 (d, J =6.1 Hz, 1H), 3.84 (d, J = 11.8 Hz, 2H), 3.57 (d, J = 12.0 Hz, 2H), 2.49(s, 2H), 2.03-1.95 (m, 2H), 1.90 (d, J = 7.0 Hz, 3H), 1.81-1.66 (m, 2H),1.38 (s, 6H). 87 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz,1H), 8.72 (d, J = 2.2 Hz, 1H), 8.57 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H),7.66 (s, 1H), 7.44 (d, J = 6.3 Hz, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.22(dt, J = 13.1, 6.7 Hz, 3H), 4.80 (dd, J = 6.6, 5.1 Hz, 2H), 4.01 (d, J =6.0 Hz, 1H), 3.87 (dd, J = 12.4, 3.2 Hz, 2H), 3.59 (d, J = 11.8 Hz, 2H),2.51 (s, 2H), 2.10-1.88 (m, 2H), 1.83-1.67 (m, 2H), 1.40 (s, 6H). 88 1HNMR (400 MHz, Methanol-d4) δ 8.71 (d, J = 2.2 Hz, 1H), 8.67 (s, 1H),8.64 (d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.19(d, J = 5.0 Hz, 1H), 4.24 (hept, J = 6.1 Hz, 1H), 4.04 (q, J = 9.0 Hz,1H), 2.82 (q, J = 9.1 Hz, 1H), 2.51-2.32(m, 1H), 2.30-2.18 (m, 1H),2.17-2.06 (m, 1H), 2.05-1.90 (m, 1H), 1.48 (d, J = 6.4 Hz, 6H), 1.17 (s,3H), 1.13 (s, 3H). 89 1H NMR (400 MHz, Methanol-d4) δ 8.60 (s, 1H), 8.57(d, J = 2.3 Hz, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H), 7.85 (d, J= 4.9 Hz, 1H), 7.10 (d, J = 4.9 Hz, 1H), 4.17-3.97 (m, 1H), 2.31-2.13(m, 6H), 1.91-1.80 (m, 6H), 1.43 (d, J = 6.4 Hz, 6H). 90 1H NMR (400MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H),8.48 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.50 (d, J = 6.1Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.29 (p, J = 6.4 Hz, 1H), 4.14 (q, J= 6.8 Hz, 1H), 4.01 (d, J = 6.0 Hz, 1H), 3.82 (dd, J = 12.1, 3.1 Hz,2H), 3.56 (d, J = 11.9 Hz, 2H), 2.49 (s, 2H), 2.02-1.96 (m, 2H),1.81-1.65 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H), 1.36 (d, J = 6.8 Hz, 3H).91 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J= 2.1 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H),7.50 (d, J = 6.1 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.29 (p, J = 6.4 Hz,1H), 4.14 (q, J = 6.7 Hz, 1H), 4.01 (d, J = 5.9 Hz, 1H), 3.82 (dd, J =12.3, 3.1 Hz, 2H), 3.56 (d, J = 11.9 Hz, 2H), 2.49 (s, 2H), 2.03-1.96(m, 2H), 1.79-1.65 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H), 1.36 (d, J = 6.8Hz, 3H). 92 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H),8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.87(s, 1H), 7.79 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.28 (h, J= 6.6 Hz, 1H), 4.01-3.93 (m, 1H), 3.80 (dd, J = 12.3, 3.1 Hz, 2H),3.61-3.48 (m, 2H), 3.20-3.10 (m, 1H), 2.44 (s, 2H), 2.34-2.16 (m, 4H),2.04-1.94 (m, 2H), 1.73-1.59 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H), 1.34 (s,3H). 93 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68(d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.86 (s,1H), 7.81 (d, J = 5.6 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (p, J =6.4 Hz, 1H), 4.01-3.92 (m, 1H), 3.80 (dd, J = 12.3, 3.1 Hz, 2H), 3.54(d, J = 11.9 Hz, 2H), 2.67 (p, J = 8.5 Hz, 1H), 2.43 (s, 2H), 2.35-2.24(m, 2H), 2.22-2.11 (m, 2H), 2.06-1.93 (m, 2H), 1.76-1.61 (m, 2H), 1.47(d, J = 6.4 Hz, 6H), 1.36 (s, 3H). 94 1H NMR (400 MHz, Methanol-d4) δ8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.07(d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J = 5.1 Hz, 1H), 7.23 (d, J= 5.0 Hz, 1H), 4.41 (d, J = 6.2 Hz, 2H), 4.29 (p, J = 6.4 Hz, 1H),4.03-3.94 (m, 1H), 3.82 (dd, J = 12.3, 3.1 Hz, 2H), 3.56 (d, J = 11.7Hz, 2H), 2.51 (s, 2H), 2.06-1.92 (m, 2H), 1.75-1.65 (m, 2H), 1.60 (s,3H), 1.47 (d, J = 6.4 Hz, 6H). 95 1H NMR (400 MHz, Methanol-d4) δ 8.76(d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.07 (d, J= 5.1 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 7.17 (d, J = 4.5Hz, 1H), 4.29 (hept, J = 6.5 Hz, 1H), 4.00-3.92 (m, 1H), 3.87-3.73 (m,4H), 3.61-3.47 (m, 4H), 2.55 (s, 2H), 2.14-2.03 (m, 2H), 2.03-1.96 (m,2H), 1.76-1.64 (m, 2H), 1.53 (ddd, J = 13.7, 9.6, 3.9 Hz, 2H), 1.47 (d,J = 6.4 Hz, 6H), 1.24 (s, 3H). 96 1H NMR (400 MHz, Methanol-d4) δ 8.76(d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.49 (s, 1H), 8.07 (d, J= 5.1 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.38-4.10 (m,3H), 3.88 (s, 1H), 3.80 (dd, J = 12.2, 3.1 Hz, 2H), 3.62-3.44 (m, 4H),3.25-3.02 (m, 4H), 2.94 (s, 3H), 2.50 (s, 2H), 2.11-1.96 (m, 2H),1.73-1.61 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). Additional peak obscured bysolvent. 97 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H),8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.86(s, 1H), 7.47 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.29 (p, J= 6.4 Hz, 1H), 3.96 (s, 1H), 3.81 (dd, J = 12.3, 3.1 Hz, 2H), 3.54 (d, J= 11.9 Hz, 2H), 2.53 (s, 2H), 2.08-1.95 (m, 2H), 1.77-1.63 (m, 2H), 1.47(d, J = 6.4 Hz, 6H), 1.44 (s, 6H). 98 1H NMR (400 MHz, Methanol-d4) δ8.76 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.07(d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (p, J= 6.4 Hz, 1H), 4.05 (s, 1H), 3.89 (s, 2H), 3.82 (dd, J = 12.4, 3.1 Hz,2H), 3.59-3.51 (m, 2H), 3.45 (s, 6H), 2.48 (s, 2H), 2.07-1.96 (m, 2H),1.83-1.65 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 99 1H NMR (400 MHz,Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.52(s, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.65 (s, 1H), 7.23 (d, J = 5.0 Hz,1H), 4.99 (d, J = 6.6 Hz, 2H), 4.85 (d, J = 6.7 Hz, 2H), 4.02 (s, 2H),3.94 (s, 2H), 3.75-3.60 (m, 1H), 2.17-2.04 (m, 2H), 1.94-1.92 (m, 6H),1.93-1.81 (m, 2H), 1.73 (td, J = 12.9, 3.6 Hz, 2H), 1.41-1.23 (m, 2H).100 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.67 (d, J= 2.2 Hz, 1H), 8.49 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 8.02 (d, J = 5.6Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (hept, J = 6.7 Hz,1H), 3.98 (d, J = 5.5 Hz, 1H), 3.90-3.76 (m, 2H), 3.66-3.51 (m, 4H),3.09-2.94 (m, 2H), 2.88 (s, 3H), 2.64-2.49 (m, 1H), 2.45 (s, 2H),2.13-1.87 (m, 6H), 1.77-1.61 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 101 1HNMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2Hz, 1H), 8.51 (s, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.91 (s, 1H), 7.42 (d,J = 6.2 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.36-4.21 (m, 1H), 4.03 (dt,J = 12.0, 4.0 Hz, 2H), 3.98 (d, J = 6.2 Hz, 1H), 3.84 (dd, J = 12.3, 3.1Hz, 2H), 3.76-3.67 (m, 2H), 3.58 (s, 1H), 3.55 (s, 1H), 2.49 (s, 2H),2.25-2.13 (m, 2H), 2.03-1.93 (m, 2H), 1.86-1.67 (m, 4H), 1.38 (s, 6H).102 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.67 (d, J= 2.2 Hz, 1H), 8.50 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.88 (s, 1H),7.23 (d, J = 5.1 Hz, 1H), 4.30 (h, J = 6.5 Hz, 1H), 3.97-3.78 (m, 3H),3.65-3.53 (m, 2H), 3.06 (br s, 8H), 2.49 (s, 2H), 2.06-1.99 (m, 2H),1.86-1.77 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 103 1H NMR (400 MHz,Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.48(s, 1H), 8.12 (d, J = 5.9 Hz, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.87 (s,1H), 7.23 (d, J = 5.1 Hz, 1H), 4.29 (p, J = 6.5 Hz, 1H), 4.04 (d, J =5.5 Hz, 1H), 3.84 (dd, J = 12.4, 3.1 Hz, 2H), 3.57 (d, J = 12.0 Hz, 2H),3.46 (s, 6H), 2.57 (s, 2H), 2.12-1.97 (m, 2H), 1.81-1.64 (m, 2H), 1.47(d, J = 6.4 Hz, 6H). 104 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J =2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.0Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (p, J = 6.4 Hz,1H), 3.88 (s, 1H), 3.80 (dd, J = 12.3, 3.1 Hz, 2H), 3.66-3.52 (m, 6H),3.51-3.47 (m, 2H), 3.45-3.39 (m, 2H), 2.50 (s, 2H), 2.13 (s, 3H),2.08-2.00 (m, 2H), 1.72-1.59 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). 105 1HNMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.23 (d,J = 5.1 Hz, 1H), 4.29 (p, J = 6.3 Hz, 1H), 3.87 (s, 1H), 3.80 (dd, J =12.3, 3.1 Hz, 2H), 3.71 (s, 3H), 3.54 (d, J = 11.8 Hz, 2H), 3.50-3.39(m, 8H), 2.49 (s, 2H), 2.11-1.96 (m, 2H), 1.73-1.58 (m, 2H), 1.47 (d, J= 6.4 Hz, 6H). 106 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz,1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H),7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (p, J = 6.4 Hz, 1H), 3.87(s, 1H), 3.80 (dd, J = 12.3, 3.1 Hz, 2H), 3.58-3.48 (m, 6H), 3.26-3.18(m, 4H), 2.86 (s, 3H), 2.50 (s, 2H), 2.11-1.95 (m, 2H), 1.73-1.61 (m,2H), 1.47 (d, J = 6.4 Hz, 6H). 107 1H NMR (400 MHz, Methanol-d4) δ 8.77(d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.07 (d, J= 5.0 Hz, 1H), 7.88 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.65 (s, 1H),4.30 (p, J = 6.2 Hz, 1H), 4.17 (dd, J = 32.3, 11.3 Hz, 2H), 3.96-3.76(m, 4H), 3.30 (s, 6H), 3.02 (s, 1H), 2.98-2.91 (m, 1H), 1.85 (d, J = 9.3Hz, 1H), 1.48 (d, J = 6.4 Hz, 6H). 108 1H NMR (400 MHz, Methanol-d4) δ8.76 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 8.07(d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.49 (d, J= 6.4 Hz, 2H), 4.35-4.19 (m, 3H), 4.20-3.0 (br m, 8H), 3.73 (d, J = 11.3Hz, 2H), 2.97-2.81 (m, 4H), 1.75 (d, J = 9.2 Hz, 1H), 1.47 (d, J = 6.4Hz, 6H). 109 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H),8.72 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.65(s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 5.00 (d, J = 6.6 Hz, 2H), 4.85 (d, J= 6.6 Hz, 2H), 4.05 (s, 1H), 3.85 (s, 3H), 3.82 (d, J = 3.1 Hz, 1H),3.56 (d, J = 11.9 Hz, 2H), 3.39 (s, 6H), 2.48 (s, 2H), 2.07-1.97 (m,2H), 1.93 (s, 3H), 1.78-1.66 (m, 2H). 110 1H NMR (400 MHz, Methanol-d4)δ 8.76 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 7.94(d, J = 5.1 Hz, 1H), 7.66 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 5.00 (d, J= 6.6 Hz, 2H), 4.85 (d, J = 6.6 Hz, 2H), 4.23 (s, 2H), 3.88 (s, 1H),3.82 (dd, J = 12.3, 3.2 Hz, 2H), 3.54 (d, J = 11.8 Hz, 3H), 2.94 (s,3H), 2.50 (s, 2H), 2.09-1.98 (m, 2H), 1.92 (s, 3H), 1.76-1.61 (m, 2H).111 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.72 (d, J= 2.2 Hz, 1H), 8.57 (s, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H),7.23 (d, J = 5.0 Hz, 1H), 5.01 (d, J = 6.6 Hz, 2H), 4.88-4.85 (m, 2H),4.75 (s, 1H), 4.60 (s, 1H), 4.12 (d, J = 10.9 Hz, 1H), 4.07 (d, J = 12.9Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H), 3.79 (d, J = 10.8 Hz, 1H), 2.99-2.87(m, 1H), 1.99 (s, 3H), 1.93 (s, 3H), 1.82 (d, J = 9.2 Hz, 1H). 112 1HNMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.58 (s, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.23 (d,J = 5.1 Hz, 1H), 5.11 (s, 1H), 5.01 (d, J = 6.6 Hz, 2H), 4.87-4.86 (m,2H), 4.59 (s, 1H), 4.24 (d, J = 11.1 Hz, 1H), 4.13 (d, J = 11.2 Hz, 1H),3.89 (d, J = 11.0 Hz, 1H), 3.81 (d, J = 11.1 Hz, 1H), 2.96-2.87 (m, 1H),1.93 (s, 3H), 1.80 (d, J = 9.3 Hz, 1H), 1.44 (s, 3H), 1.29 (s, 3H). 1131H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.72 (d, J =2.2 Hz, 1H), 8.58 (s, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.23(d, J = 5.1 Hz, 1H), 5.01 (d, J = 6.6 Hz, 2H), 4.92 (s, 1H), 4.87-4.85(m, 2H), 4.65 (s, 1H), 4.21 (d, J = 11.6 Hz, 1H), 4.13 (d, J = 11.0 Hz,1H), 3.94-3.78 (m, 4H), 3.29 (s, 6H), 2.99-2.90 (m, 1H), 1.93 (s, 3H),1.85 (d, J = 9.2 Hz, 1H). 114 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J= 2.1 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 7.94 (d, J = 5.1Hz, 1H), 7.70 (s, 1H), 7.22 (d, J = 5.1 Hz, 1H), 5.00 (d, J = 6.6 Hz,2H), 4.89-4.86 (m, 3H), 4.50 (d, J = 6.4 Hz, 2H), 4.24 (d, J = 11.2 Hz,2H), 3.74 (d, J = 11.3 Hz, 2H), 2.94 (s, 3H), 2.92-2.79 (m, 1H), 1.93(s, 3H), 1.76 (d, J = 9.2 Hz, 1H). 115 1H NMR (400 MHz, Methanol-d4) δ8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.67 (s, 1H), 8.13(d, J = 5.1 Hz, 1H), 8.08 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.25 (q, J= 6.9 Hz, 1H), 5.12 (s, 1H), 4.60 (s, 1H), 4.25 (d, J = 11.1 Hz, 1H),4.14 (d, J = 10.8 Hz, 1H), 3.90 (d, J = 11.4 Hz, 1H), 3.82 (d, J = 10.9Hz, 1H), 2.92 (q, J = 7.3 Hz, 1H), 1.91 (d, J = 7.0 Hz, 3H), 1.81 (d, J= 9.3 Hz, 1H), 1.44 (s, 3H), 1.30 (s, 3H). 116 1H NMR (400 MHz,Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.49(s, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.0 Hz,1H), 4.92-4.83 (m, 2H), 4.82-4.76 (m, 2H), 4.38-4.25 (m, 2H), 3.88 (s,1H), 3.80 (dd, J = 12.3, 3.1 Hz, 2H), 3.71 (s, 4H), 3.60-3.51 (m, 2H),3.18-3.08 (m, 4H), 2.49 (s, 2H), 2.08-1.95 (m, 2H), 1.72-1.62 (m, 2H),1.47 (d, J = 6.4 Hz, 6H). 117 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J= 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 8.07 (d, J = 5.1Hz, 1H), 7.90 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.91-4.84(m, 1H), 4.62(s, 1H), 4.29 (p, J = 6.4 Hz, 1H), 4.16-4.02 (m, 2H), 3.97 (d, J = 12.2Hz, 1H), 3.81 (d, J = 10.9 Hz, 1H), 3.57 (t, J = 14.1 Hz, 2H), 3.11-2.97(m, 2H), 2.88 (s, 5H), 2.78-2.63 (m, 1H), 2.21-2.09 (m, 1H), 2.00-1.82(m, 3H), 1.47 (d, J = 6.3 Hz, 6H). 118 1H NMR (400 MHz, Methanol-d4) δ8.73 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 7.94(d, J = 5.0 Hz, 1H), 7.72 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 4.99 (d, J= 6.6 Hz, 2H), 4.90-4.83 (m, 3H), 4.62 (s, 1H), 4.09 (t, J = 12.0 Hz,2H), 3.96 (d, J = 12.0 Hz, 1H), 3.82 (d, J = 11.0 Hz, 1H), 3.57 (t, J =13.8 Hz, 2H), 3.11-2.97 (m, 2H), 2.88 (s, 4H), 2.79-2.64 (m, 1H),2.22-2.09 (m, 1H), 1.99-1.83 (m, 7H). 119 1H NMR (400 MHz, Methanol-d4)δ 8.74 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.00(d, J = 5.7 Hz, 1H), 7.93 (d, J = 5.0 Hz, 1H), 7.68 (s, 1H), 7.21 (d, J= 5.1 Hz, 1H), 5.00 (d, J = 6.6 Hz, 2H), 4.83 (s, 1H), 3.99 (d, J = 5.4Hz, 1H), 3.82 (dd, J = 12.2, 3.1 Hz, 2H), 3.65-3.50 (m, 4H), 3.45-3.36(m, 1H), 3.08-2.96 (m, 2H), 2.93-2.85 (m, 3H), 2.63-2.50 (m, 1H), 2.45(s, 2H), 2.10-1.94 (m, 5H), 1.96-1.86 (m, 4H), 1.75-1.65 (m, 2H). 120 1HNMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.71 (s, 1H),8.69 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.24(d, J = 5.1 Hz, 1H), 4.31 (p, J = 6.3 Hz, 1H), 2.27-2.09 (m, 12H), 1.49(d, J = 6.4 Hz, 6H), 1.34 (s, 6H). 121 1H NMR (400 MHz, Methanol-d4) δ8.77 (d, J = 2.2 Hz, 1H), 8.71 (s, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.08(d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 4.31 (p, J= 6.4 Hz, 1H), 3.73 (s, 2H), 3.36 (s, 6H), 2.30-2.09 (m, 12H), 1.49 (d,J = 6.4 Hz, 6H). 122 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2Hz, 1H), 8.71 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 5.1 Hz,1H), 7.96 (s, 1H), 7.68 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (p, J =6.3 Hz, 1H), 3.56 (d, J = 12.0 Hz, 2H), 3.08-2.94 (m, 2H), 2.87 (s, 3H),2.55-2.37 (m, 1H), 2.28-2.07 (m, 12H), 2.06-1.96 (m, 2H), 1.96-1.80 (m,2H), 1.48 (d, J = 6.4 Hz, 6H). 123 1H NMR (400 MHz, Methanol-d4) δ 8.76(d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.07 (d, J= 5.0 Hz, 1H), 7.90 (d, J = 5.6 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.1Hz, 1H), 4.54 (d, J = 13.3 Hz, 1H), 4.29 (p, J = 6.4 Hz, 1H), 4.09-3.92(m, 2H), 3.86-3.75 (m, 2H), 3.54 (d, J = 12.0 Hz, 2H), 3.23-3.10 (m,1H), 2.68 (td, J = 12.9, 2.9 Hz, 1H), 2.53 (tt, J = 11.4, 3.9 Hz, 1H),2.44 (s, 2H), 2.11 (s, 3H), 2.06-1.97 (m, 2H), 1.88-1.74 (m, 2H),1.74-1.63 (m, 3H), 1.58 (qd, J = 12.6, 4.4 Hz, 1H), 1.47 (d, J = 6.4 Hz,6H). 124 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.68(d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 8.03 (d, J= 5.5 Hz, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.79 (dd, J =8.3, 5.7 Hz, 2H), 4.39 (s, 1H), 4.29 (p, J = 6.5 Hz, 1H), 3.99 (d, J =5.4 Hz, 1H), 3.81 (dd, J = 12.4, 3.1 Hz, 2H), 3.62-3.51 (m, 3H),2.95-2.81 (m, 2H), 2.68-2.53 (m, 1H), 2.45 (s, 2H), 2.19-1.91 (m, 7H),1.77-1.64 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H). Additional peak obscured bysolvent. 125 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H),8.73 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 5.2 Hz, 1H), 8.00(s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.31 (q, J = 6.3 Hz, 1H), 3.85-3.71(m, 1H), 3.31-3.26 (m, 1H), 2.33 (d, J = 13.2 Hz, 2H), 2.12 (d, J = 12.8Hz, 2H), 1.89-1.74 (m, 2H), 1.63-1.45 (m, 9H), 0.87 (dt, J = 4.7, 3.1Hz, 2H), 0.83-0.70 (m, 2H). 126 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d,J = 2.2 Hz, 1H), 8.74 (s, 1H), 8.72 (s, 1H), 8.10 (d, J = 5.0 Hz, 1H),7.97 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.34 (p, J = 6.4 Hz, 1H), 3.66(s, 3H), 3.57-3.46 (m, 1H), 3.32-3.25 (m, 1H), 2.33 (d, J = 13.1 Hz,2H), 2.14 (d, J = 12.8 Hz, 2H), 1.88-1.71 (m, 2H), 1.60-1.44 (m, 8H).127 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.2 Hz, 1H), 8.75 (s,1H), 8.72 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 5.0 Hz, 1H), 7.98 (s, 1H),7.26 (d, J = 5.0 Hz, 1H), 4.35 (h, J = 6.4 Hz, 1H), 4.07-3.90 (m, 1H),3.48 (dd, J = 8.6, 4.2 Hz, 1H), 2.22-2.08 (m, 4H), 1.98 (s, 3H),1.90-1.74 (m, 4H), 1.52 (d, J = 6.4 Hz, 6H). 128 1H NMR (400 MHz,Methanol-d4) δ 8.80 (d, J = 2.2 Hz, 1H), 8.75 (s, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 7.98 (s, 1H), 7.26 (d, J = 5.1 Hz,1H), 4.63 (d, J = 13.6 Hz, 1H), 4.35 (p, J = 6.4 Hz, 1H), 4.10 (d, J =13.9 Hz, 1H), 3.64 (tt, J = 11.4, 3.9 Hz, 1H), 3.45-3.35 (m, 1H),3.04-2.90 (m, 1H), 2.39-2.22 (m, 2H), 2.18 (s, 3H), 1.89 (dqd, J = 48.9,12.0, 4.3 Hz, 2H), 1.51 (d, J = 6.4 Hz, 6H). 129 1H NMR (400 MHz,Methanol-d4) δ 8.80 (d, J = 2.2 Hz, 1H), 8.77 (s, 1H), 8.71 (d, J = 2.2Hz, 1H), 8.11 (d, J = 5.0 Hz, 1H), 8.01 (s, 1H), 7.26 (d, J = 5.0 Hz,1H), 4.41-4.25 (m, 1H), 3.84-3.65 (m, 1H), 3.65-3.50 (m, 2H), 3.26 (d, J= 12.6 Hz, 2H), 2.50 (d, J = 14.2 Hz, 2H), 2.29-2.12 (m, 2H), 1.51 (d, J= 6.4 Hz, 6H). 130 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz,1H), 8.69 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.08 (d, J =5.0 Hz, 1H), 7.94 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.36-4.24 (m, 1H),3.95 (t, J = 5.3 Hz, 4H), 3.49 (q, J = 5.3, 4.2 Hz, 4H), 1.49 (d, J =6.4 Hz, 6H). 131 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz,1H), 8.70 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H),7.90 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.38-4.23 (m, 1H), 3.92-3.84 (m,4H), 3.71-3.60 (m, 4H), 1.49 (d, J = 6.4 Hz, 6H). 132 1H NMR (400 MHz,Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.68(s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.96 (s, 1H), 7.26 (d, J = 5.1 Hz,1H), 4.40-4.23 (m, 1H), 2.63 (dt, J = 9.1, 4.8 Hz, 1H), 1.81 (ddd, J =9.3, 6.7, 4.6 Hz, 1H), 1.56-1.43 (m, 7H), 1.43-1.28 (m, 7H). 132 Isomer1 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.74-8.64(m, 2H), 8.10 (d, J = 5.1 Hz, 1H), 7.97 (s, 1H), 7.25 (d, J = 5.1 Hz,1H), 4.32 (hept, J = 6.4 Hz, 1H), 2.63 (dt, J = 8.7, 4.8 Hz, 1H), 1.81(ddd, J = 9.3, 6.7, 4.7 Hz, 1H), 1.55-1.46 (m, 7H), 1.43-1.28 (m, 7H).132 Isomer 2 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H),8.73-8.67 (m, 2H), 8.10 (d, J = 5.1 Hz, 1H), 7.97 (s, 1H), 7.25 (d, J =5.1 Hz, 1H), 4.42-4.22 (m, 1H), 2.63 (dt, J = 8.7, 4.9 Hz, 1H), 1.80(ddd, J = 9.3, 6.7, 4.7 Hz, 1H), 1.54-1.46 (m, 7H), 1.40-1.27 (m, 7H).133 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.75 (s,1H), 8.70 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 5.0 Hz, 1H), 8.02 (s, 1H),7.25 (d, J = 5.0 Hz, 1H), 6.30 (t, J = 54.4 Hz, 1H), 4.33 (hept, J = 6.4Hz, 1H), 3.65-3.39 (m, 5H), 3.13-2.96 (m, 2H), 2.48-2.37 (m, 2H),2.30-2.14 (m, 2H), 1.51 (d, J = 6.4 Hz, 6H). 134 1H NMR (400 MHz,Methanol-d4) δ 8.86-8.78 (m, 2H), 8.74 (s, 1H), 8.08 (d, J = 5.1 Hz,1H), 7.93 (s, 1H), 7.27 (d, J = 5.1 Hz, 1H), 4.62 (t, J = 7.4 Hz, 1H),3.87-3.74 (m, 1H), 3.71 (s, 3H), 3.41 (d, J = 7.3 Hz, 2H), 2.72-2.47 (m,3H), 2.36 (t, J = 10.8 Hz, 5H), 2.13 (d, J = 12.9 Hz, 2H), 1.90-1.70 (m,2H), 1.66-1.43 (m, 3H), 0.94-0.72 (m, 4H). 135 1H NMR (400 MHz,Methanol-d4) δ 8.86-8.76 (m, 2H), 8.74 (d, J = 2.2 Hz, 1H), 8.09 (d, J =5.0 Hz, 1H), 7.75 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 5.34-5.13 (m, 3H),4.86-4.80 (m, 3H), 3.86-3.71 (m, 1H), 2.35 (d, J = 13.1 Hz, 2H), 2.13(d, J = 12.8 Hz, 2H), 1.83 (d, J = 12.7 Hz, 1H), 1.64-1.46 (m, 3H),0.92-0.82 (m, 2H), 0.78 (dt, J = 8.1, 3.2 Hz, 2H). 136 1H NMR (400 MHz,Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.77-8.72 (m, 2H), 8.08 (d, J =5.1 Hz, 1H), 7.73 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.37-5.13 (m, 3H),4.82 (dd, J = 6.7, 5.3 Hz, 2H), 2.65 (dt, J = 8.7, 4.9 Hz, 1H), 1.82(ddd, J = 9.3, 6.7, 4.6 Hz, 1H), 1.54 (ddd, J = 8.8, 6.8, 4.7 Hz, 1H),1.46-1.24 (m, 7H). 136 Isomer 1 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d,J = 2.2 Hz, 1H), 8.76-8.68 (m, 2H), 8.08 (d, J = 5.0 Hz, 1H), 7.74 (s,1H), 7.25 (d, J = 5.1 Hz, 1H), 5.33-5.14 (m, 3H), 4.82 (dd, J = 6.6, 5.1Hz, 2H), 2.70-2.60 (m, 1H), 1.82 (ddd, J = 9.3, 6.7, 4.7 Hz, 1H),1.59-1.48 (m, 1H), 1.45-1.26 (m, 7H). 136 Isomer 2 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.75-8.68 (m, 2H), 8.07 (d, J =5.1 Hz, 1H), 7.76 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 5.34-5.16 (m, 3H),4.84-4.79 (m, 2H), 2.65 (dt, J = 9.0, 4.8 Hz, 1H), 1.86-1.76 (m, 1H),1.53 (t, J = 6.8 Hz, 1H), 1.44-1.28 (m, 7H). 136 Isomer 3 1H NMR (400MHz, Methanol-d4) δ 8.76-8.71 (m, 2H), 8.70 (d, J = 2.2 Hz, 1H), 8.04(d, J = 5.0 Hz, 1H), 7.81 (s, 1H), 7.22 (d, J = 5.0 Hz, 1H),5.25-5.17(m, 3H), 4.84-4.78 (m, 2H), 2.63-2.51 (m, 1H), 1.74-1.64 (m,1H), 1.59-1.50 (m, 1H), 1.50-1.41 (m, 1H), 1.39-1.32 (m, 6H). 136 Isomer4 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.74-8.64(m, 2H), 8.04 (d, J = 5.0 Hz, 1H), 7.80 (s, 1H), 7.22 (d, J = 5.0 Hz,1H), 5.25-5.17 (m, 3H), 4.84-4.78 (m, 2H), 2.59 (td, J = 8.7, 6.3 Hz,1H), 1.78-1.65 (m, 1H), 1.61-1.52 (m, 1H), 1.52-1.42 (m, 1H), 1.39-1.32(m, 6H). 137 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H),8.70 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.27 (d, J = 4.6 Hz, 1H), 8.09(d, J = 5.1 Hz, 1H), 7.88 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.41 (s,1H), 4.38-4.25 (m, 1H), 4.07 (s, 1H), 3.79 (d, J = 9.2 Hz, 1H), 2.72 (s,1H), 2.03 (s, 6H), 1.65 (s, 1H), 1.49 (d, J = 6.3 Hz, 7H). 138 1H NMR(400 MHz, Methanol-d4) δ 8.83-8.75 (m, 2H), 8.71 (d, J = 2.2 Hz, 1H),8.11 (d, J = 5.0 Hz, 1H), 8.01 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H),4.99-4.77 (m, 5H), 4.55-4.41 (m, 1H), 4.35 (hept, J = 6.5 Hz, 1H),3.85-3.54 (m, 3H), 3.26-3.04 (m, 1H), 2.64-2.51 (m, 2H), 2.44-2.20 (m,2H), 1.51 (d, J = 6.4 Hz, 6H). 139 1H NMR (400 MHz, Methanol-d4) δ 8.80(d, J = 2.1 Hz, 1H), 8.74 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.10 (d, J= 5.0 Hz, 1H), 7.97 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.34 (hept, J =6.5 Hz, 1H), 3.75-3.63 (m, 5H), 3.44-3.36 (m, 5H), 2.33 (d, J = 13.1 Hz,2H), 2.12 (d, J = 12.7 Hz, 2H), 1.91-1.75 (m, 2H), 1.64-1.42 (m, 8H).140 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.74 (s,1H), 8.71 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 5.0 Hz, 1H), 7.97 (s, 1H),7.26 (d, J = 5.1 Hz, 1H), 4.34 (p, J = 6.4 Hz, 1H), 3.66-3.52 (m, 1H),3.31-3.25 (m, 1H), 2.73 (s, 3H), 2.32 (d, J = 13.2 Hz, 2H), 2.14 (d, J =12.8 Hz, 2H), 1.88-1.69 (m, 2H), 1.57-1.36 (m, 8H). 141 1H NMR (400 MHz,Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.54(s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.91 (s, 1H), 7.25 (d, J = 5.1 Hz,1H), 4.50 (dt, J = 20.9, 4.7 Hz, 2H), 4.38-4.23 (m, 2H), 2.45 (s, 1H),2.09-1.92 (m, 6H), 1.92-1.81 (m, 1H), 1.81-1.67 (m, 1H), 1.49 (d, J =6.4 Hz, 6H), 1.42 (dd, J = 12.8, 4.7 Hz, 1H). 142 1H NMR (400 MHz,Methanol-d4) δ 8.85-8.79 (m, 2H), 8.74 (d, J = 2.2 Hz, 1H), 8.10 (dd, J= 5.1, 1.5 Hz, 1H), 7.75 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H),5.37-5.07 (m, 3H), 4.86-4.73 (m, 2H), 3.76-3.57 (m, 5H), 3.43-3.37 (m,5H), 2.40-2.29 (m, 2H), 2.19-2.07 (m, 2H), 1.92-1.71 (m, 2H), 1.62-1.47(m, 2H). 143 1H NMR (400 MHz, Methanol-d4) δ 8.84-8.76 (m, 2H), 8.74 (s,1H), 8.08 (d, J = 5.0 Hz, 1H), 7.93 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H),4.67-4.50 (m, 1H), 3.77-3.61 (m, 8H), 3.46-3.26 (m, 7H), 2.71-2.49 (m,3H), 2.46-2.25 (m, 4H), 2.13 (d, J = 12.6 Hz, 2H), 1.90-1.75 (m, 2H),1.63-1.47 (m, 2H). 144 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 7.96 (d, J = 5.1 Hz,1H), 7.67 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.02 (d, J = 6.6 Hz, 2H),4.87 (d, J = 6.7 Hz, 2H), 4.04-3.99 (m, 1H), 3.83 (dd, J = 12.3, 3.1 Hz,2H), 3.57 (d, J = 11.9 Hz, 2H), 2.50-2.41 (m, 2H), 2.09-2.01 (m, 2H),2.00 (s, 3H), 1.95 (s, 3H), 1.70 (d, J = 8.3 Hz, 2H). 145 1H NMR (400MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H),8.54 (s, 1H), 7.95 (d, J = 5.1 Hz, 1H), 7.70 (s, 1H), 7.24 (d, J = 5.1Hz, 1H), 5.02 (d, J = 6.6 Hz, 2H), 4.86 (d, J = 6.6 Hz, 2H), 4.57-4.49(m, 2H), 3.68 (d, J = 12.1 Hz, 2H), 3.62-3.53 (m, 2H), 2.12-2.03 (m,2H), 1.98-1.91 (m, 5H). 146 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J =2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.50 (s, 1H), 8.08 (d, J = 5.1Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.36-4.23 (m, 1H), 4.15(t, J = 5.2 Hz, 1H), 3.83 (d, J = 11.9 Hz, 2H), 3.59-3.50 (m, 2H),2.29-2.19 (m, 2H), 1.97-1.83 (m, 2H), 1.75-1.63 (m, 2H), 1.49 (d, J =6.4 Hz, 6H). 147 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz,1H), 8.75 (d, J = 2.2 Hz, 1H), 8.57 (s, 1H), 7.96 (d, J = 5.0 Hz, 1H),7.67 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.03 (d, J = 6.6 Hz, 2H), 4.87(d, J = 6.6 Hz, 2H), 4.67-4.50 (m, 1H), 4.50-4.36 (m, 1H), 4.13 (d, J =13.8 Hz, 1H), 3.80 (dd, J = 29.4, 14.1 Hz, 1H), 3.67-3.55 (m, 1H),2.13-1.98 (m, 5H), 1.95 (s, 3H). 147 Isomer 1 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.57(s, 1H), 8.54-8.49 (m, 1H), 7.96 (d, J = 5.1 Hz, 1H), 7.69 (s, 1H), 7.25(d, J = 5.1 Hz, 1H), 5.02 (d, J = 6.6 Hz, 2H), 4.87 (d, J = 6.7 Hz, 2H),4.67-4.50 (m, 1H), 4.42 (d, J = 9.6 Hz, 1H), 4.13 (d, J = 13.7 Hz, 1H),3.80 (dd, J = 29.4, 14.1 Hz, 1H), 3.62 (t, J = 12.2 Hz, 1H), 2.00 (d, J= 38.6 Hz, 8H). 147 Isomer 2 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J= 2.2 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.56 (s, 1H), 8.54-8.47 (m,1H), 7.95 (d, J = 5.0 Hz, 1H), 7.70 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H),5.02 (d, J = 6.6 Hz, 2H), 4.86 (d, J = 6.6 Hz, 2H), 4.69-4.35 (m, 2H),4.13 (d, J = 13.4 Hz, 1H), 3.80 (dd, J = 29.5, 14.0 Hz, 1H), 3.61 (t, J= 12.5 Hz, 1H), 2.16-1.86 (m, 8H). 148 1H NMR (400 MHz, Methanol-d4) δ8.79 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.64 (s, 1H),8.16-8.08 (m, 2H), 7.27 (d, J = 5.1 Hz, 1H), 5.24 (q, J = 7.0 Hz, 1H),4.02 (s, 1H), 3.84 (d, J = 12.1 Hz, 2H), 3.57 (d, J = 11.9 Hz, 2H), 2.47(s, 2H), 2.13-2.03 (m, 2H), 1.92 (d, J = 6.9 Hz, 3H), 1.77-1.60 (m, 3H),0.88 (dt, J = 6.1, 3.1 Hz, 2H), 0.79 (dt, J = 8.1, 3.2 Hz, 2H). 149 1HNMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.3 Hz, 1H), 8.74 (d, J = 2.1Hz, 1H), 8.54 (s, 1H), 7.95 (d, J = 5.0 Hz, 1H), 7.69 (s, 1H), 7.24 (d,J = 5.0 Hz, 1H), 5.02 (d, J = 6.5 Hz, 2H), 4.87 (d, J = 6.6 Hz, 2H),4.15 (t, J = 5.2 Hz, 1H), 3.88-3.78 (m, 3H), 3.56 (d, J = 11.5 Hz, 2H),2.29-2.20 (m, 2H), 1.97-1.88 (m, 4H), 1.75-1.66 (m, 2H). 150 1H NMR (400MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H),8.50 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.0Hz, 1H), 4.31 (hept, J = 6.4 Hz, 1H), 4.00 (d, J = 11.5 Hz, 1H),3.89-3.77 (m, 2H), 3.56 (d, J = 11.9 Hz, 2H), 2.51-2.45 (m, 2H),2.14-2.03 (m, 2H), 1.76-1.63 (m, 2H), 1.49 (d, J = 6.4 Hz, 6H),0.93-0.86 (m, 2H), 0.84-0.69 (m, 2H). 151 1H NMR (400 MHz, Methanol-d4)δ 8.79 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.66 (s, 1H), 8.16(s, 1H), 8.12 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.30-5.17(m, 1H), 4.66-4.29 (m, 2H), 4.14 (d, J = 14.1 Hz, 1H), 3.80 (dd, J =29.4, 13.9 Hz, 1H), 3.62 (t, J = 11.7 Hz, 1H), 2.12-1.95 (m, 5H), 1.92(d, J = 6.9 Hz, 3H). 152 1H NMR (400 MHz, Methanol-d4) δ 8.73 (s, 1H),8.70-8.60 (m, 2H), 8.28 (s, 1H), 8.05 (d, J = 4.9 Hz, 1H), 7.22 (d, J =4.9 Hz, 1H), 5.18-5.09 (m, 1H), 4.67-4.02 (m, 3H), 3.78 (dd, J = 29.2,14.0 Hz, 1H), 3.65-3.53 (m, 1H), 2.13-1.94 (m, 5H), 1.91 (d, J = 7.0 Hz,3H). 153 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70(d, J = 2.2 Hz, 1H), 8.50 (s, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.90 (s,1H), 7.25 (d, J = 5.1 Hz, 1H), 4.31 (hept, J = 12.4, 6.1 Hz, 1H), 3.89(d, J = 11.2 Hz, 2H), 3.56 (d, J = 11.3 Hz, 2H), 2.06-1.84 (m, 4H),1.74-1.60 (m, 2H), 1.49 (d, J = 6.4 Hz, 6H), 1.38 (s, 3H). 154 1H NMR(400 MHz, Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.2 Hz,1H), 8.49 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J =5.0 Hz, 1H), 4.36-4.24 (m, 1H), 4.10 (s, 1H), 3.84-3.74 (m, 2H),3.53-3.48 (m, 2H), 2.37-2.31 (m, 2H), 2.12-2.02 (m, 2H), 1.62 (d, J =8.0 Hz, 2H), 1.49 (d, J = 6.4 Hz, 6H). 155 1H NMR (400 MHz, Methanol-d4)δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.08(d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.83-7.78 (m, 1H), 7.25 (d, J = 5.0Hz, 1H), 4.37-4.24 (m, 1H), 3.78-3.61 (m, 4H), 2.78-2.66 (m, 2H),2.18-2.02 (m, 2H), 1.95 (s, 3H), 1.75-1.66 (m, 2H), 1.64 (s, 3H), 1.49(d, J = 6.4 Hz, 6H). 156 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J =2.2 Hz, 1H), 8.77 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 5.0Hz, 1H), 8.01 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.34 (dt, J = 9.6, 5.2Hz, 1H), 4.07 (dt, J = 12.0, 4.0 Hz, 2H), 3.85-3.68 (m, 3H), 2.34 (d, J= 13.1 Hz, 2H), 2.22 (d, J = 13.0 Hz, 2H), 2.13 (d, J = 12.7 Hz, 2H),1.91-1.74 (m, 4H), 1.66-1.45 (m, 3H), 0.91-0.84 (m, 2H), 0.83-0.73 (m,2H). 157 1H NMR (400 MHz, Methanol-d4) δ 8.81 (d, J = 2.1 Hz, 1H), 8.72(d, J = 2.1 Hz, 1H), 8.66 (s, 1H), 8.15 (d, J = 5.0 Hz, 1H), 8.09 (s,1H), 7.82-7.79 (m, 1H), 7.28 (d, J = 5.1 Hz, 1H), 5.27 (q, J = 6.9 Hz,1H), 3.77-3.66 (m, 4H), 2.76-2.70 (m, 2H), 2.15-2.04 (m, 2H), 1.95 (s,3H), 1.92 (d, J = 6.9 Hz, 3H), 1.73-1.66 (m, 2H), 1.64 (s, 3H). 158 1HNMR (400 MHz, Methanol-d4) δ 8.83-8.70 (m, 3H), 7.98 (d, J = 5.1 Hz,1H), 7.75 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.05 (d, J = 6.6 Hz, 2H),4.88 (d, J = 6.6 Hz, 2H), 3.85-3.71 (m, 1H), 2.34 (d, J = 13.1 Hz, 2H),2.13 (d, J = 12.8 Hz, 2H), 1.96 (s, 3H), 1.92-1.69 (m, 3H), 1.66-1.42(m, 4H), 0.96-0.82 (m, 2H), 0.78 (dt, J = 8.2, 3.2 Hz, 2H). 159 1H NMR(400 MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz,1H), 8.52 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J =5.0 Hz, 1H), 4.32 (p, J = 6.4 Hz, 1H), 3.95-3.87 (m, 2H), 3.69 (d, J =11.4 Hz, 2H), 2.52-2.47 (m, 2H), 2.14-2.02 (m, 2H), 1.82 (d, J = 8.8 Hz,2H), 1.49 (d, J = 6.4 Hz, 6H). 160 1H NMR (400 MHz, Methanol-d4) δ 8.87(s, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.23 (s,1H), 8.14 (d, J = 5.0 Hz, 1H), 7.27 (d, J = 5.1 Hz, 1H), 5.26 (q, J =6.9 Hz, 1H), 3.88-3.71 (m, 1H), 2.35 (d, J = 13.1 Hz, 2H), 2.13 (d, J =12.9 Hz, 2H), 1.94 (d, J = 6.9 Hz, 3H), 1.83 (q, J = 10.8 Hz, 2H),1.69-1.42 (m, 3H), 0.94-0.85 (m, 2H), 0.85-0.68 (m, 2H). 161 1H NMR (400MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H),8.51 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 5.0Hz, 1H), 4.31 (hept, J = 6.4 Hz, 1H), 4.20-3.95 (m, 3H), 3.95-3.82 (m,1H), 3.82-3.67 (m, 1H), 2.15 (td, J = 11.1, 9.0, 4.1 Hz, 1H), 2.07-1.91(m, 1H), 1.49 (d, J = 6.4 Hz, 6H). 162 1H NMR (400 MHz, Methanol-d4) δ8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.52 (s, 1H), 8.09(d, J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.31 (hept,J = 6.4 Hz, 1H), 4.17-3.95 (m, 3H), 3.95-3.82 (m, 1H), 3.82-3.66 (m,1H), 2.21-2.08 (m, 1H), 2.06-1.91 (m, 1H), 1.49 (d, J = 6.4 Hz, 6H). 1631H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J =2.2 Hz, 1H), 8.51 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25(d, J = 5.0 Hz, 1H), 4.36-4.26 (m, 5H), 3.75 (s, 2H), 2.77 (s, 2H), 1.48(d, J = 6.3 Hz, 6H). 164 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J =2.1 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.09 (d, J = 5.1Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.46-4.37 (m, 2H),4.36-4.21 (m, 3H), 3.40 (t, J = 6.8 Hz, 2H), 2.61 (t, J = 6.8 Hz, 2H),1.49 (d, J = 6.4 Hz, 6H). 165 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J= 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.09 (d, J = 5.1Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.37-4.24 (m, 1H),4.05-3.99 (m, 1H), 3.84-3.78 (m, 4H), 2.23-2.13 (m, 2H), 2.04 (s, 3H),2.02-1.71 (m, 5H), 1.61-1.53 (m, 1H), 1.49 (d, J = 6.4 Hz, 6H). 166 1HNMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2Hz, 1H), 8.51 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d,J = 5.1 Hz, 1H), 4.31 (hept, J = 6.4 Hz, 1H), 4.22-4.13 (m, 1H), 4.06(d, J = 12.6 Hz, 2H), 3.76 (d, J = 12.7 Hz, 2H), 2.19-2.11 (m, 2H),2.11-1.99 (m, 4H), 1.90-1.71 (m, 3H), 1.61-1.52 (m, 1H), 1.49 (d, J =6.4 Hz, 6H). 167 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz,1H), 8.70 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H),7.91 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.36-4.23 (m, 3H), 4.09 (t, J =7.9 Hz, 2H), 3.85 (t, J = 5.0 Hz, 2H), 1.49 (d, J = 6.4 Hz, 6H). 168 1HNMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1Hz, 1H), 8.52 (s, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.91 (s, 1H), 7.25 (d,J = 5.1 Hz, 1H), 4.57 (ddd, J = 22.4, 11.3, 5.6 Hz, 1H), 4.47-4.37 (m,1H), 4.31 (p, J = 6.4 Hz, 1H), 4.13 (d, J = 13.7 Hz, 1H), 3.79 (dd, J =29.4, 14.1 Hz, 1H), 3.67-3.55 (m, 1H), 2.17-1.87 (m, 5H), 1.49 (d, J =6.4 Hz, 6H). 169 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz,1H), 8.68 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H),7.94 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 4.58 (dd, J = 22.9, 11.7 Hz,1H), 4.41 (t, J = 12.0 Hz, 1H), 4.36-4.23 (m, 1H), 4.12 (d, J = 13.5 Hz,1H), 3.79 (dd, J = 29.4, 14.1 Hz, 1H), 3.68-3.55 (m, 1H), 2.12-1.90 (m,5H), 1.49 (d, J = 6.4 Hz, 6H). 170 1H NMR (400 MHz, Methanol-d4) δ 8.78(d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.08 (d, J= 5.0 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.37-4.25 (m,1H), 4.25-4.03 (m, 5H), 2.41 (dd, J = 13.5, 7.7 Hz, 1H), 2.21-1.99 (m,3H), 1.95 (s, 3H), 1.87 (dd, J = 13.5, 7.1 Hz, 1H), 1.61 (dd, J = 12.3,6.2 Hz, 1H), 1.48 (d, J = 6.4 Hz, 6H). 171 1H NMR (400 MHz, Methanol-d4)δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.12(d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.30 (dq, J= 9.4, 4.7, 4.2 Hz, 1H), 4.04 (ddd, J = 17.0, 8.5, 4.5 Hz, 3H), 3.83(dd, J = 12.2, 3.1 Hz, 2H), 3.78-3.68 (m, 2H), 3.63-3.51 (m, 2H), 2.46(s, 2H), 2.20 (d, J = 13.1 Hz, 2H), 2.00 (s, 5H), 1.81 (ddt, J = 13.8,9.6, 5.0 Hz, 2H), 1.70 (d, J = 8.4 Hz, 2H). 172 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.50(s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.0 Hz,1H), 4.31 (hept, J = 6.4 Hz, 1H), 4.10-3.97 (m, 2H), 3.64 (td, J = 12.8,3.4 Hz, 2H), 2.09-1.86 (m, 4H), 1.49 (d, J = 6.4 Hz, 6H). 173 1H NMR(400 MHz, Methanol-d4) δ 8.81 (d, J = 5.1 Hz, 1H), 8.80-8.77 (m, 1H),8.71 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.90(s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.32 (p, J = 6.3 Hz, 1H), 4.06-3.89(m, 4H), 3.78 (t, J = 5.0 Hz, 1H), 2.78-2.66 (m, 1H), 2.62 (d, J = 6.3Hz, 2H), 2.05 (s, 3H), 1.69 (dd, J = 10.2, 5.7 Hz, 1H), 1.50 (d, J = 6.4Hz, 6H). 174 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.2 Hz, 1H),8.72 (d, J = 2.2 Hz, 1H), 8.69 (s, 1H), 8.14 (d, J = 5.1 Hz, 1H), 8.12(s, 1H), 7.27 (d, J = 5.0 Hz, 1H), 5.26 (q, J = 6.8 Hz, 1H), 4.03-3.88(m, 4H), 3.78 (d, J = 5.5 Hz, 1H), 2.72 (dd, J = 10.2, 6.2 Hz, 1H), 2.63(d, J = 6.3 Hz, 2H), 2.05 (s, 3H), 1.93 (d, J = 7.0 Hz, 3H), 1.70 (dd, J= 10.2, 5.9 Hz, 1H). 175 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J =2.2 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 7.96 (d, J = 5.1Hz, 1H), 7.68 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 5.03 (d, J = 6.6 Hz,2H), 4.88 (d, J = 6.6 Hz, 2H), 4.03-3.90 (m, 4H), 3.78 (d, J = 5.5 Hz,1H), 2.72 (dd, J = 10.6, 6.0 Hz, 1H), 2.62 (d, J = 6.3 Hz, 2H), 2.05 (s,3H), 1.95 (s, 3H), 1.69 (dd, J = 10.2, 5.8 Hz, 1H). 176 1H NMR (400 MHz,Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.53(s, 1H), 8.12 (d, J = 5.1 Hz, 1H), 7.84 (s, 1H), 7.26 (d, J = 5.1 Hz,1H), 4.02-3.90 (m, 4H), 3.77 (d, J = 5.6 Hz, 1H), 3.35 (s, 3H),2.77-2.67 (m, 1H), 2.62 (d, J = 6.3 Hz, 2H), 2.05 (s, 3H), 1.69 (dd, J =10.2, 5.8 Hz, 1H). 177 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.2Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.14 (d, J = 5.0 Hz,1H), 7.95 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.82 (d, J = 6.7 Hz, 2H),4.33 (dq, J = 9.9, 5.4, 4.9 Hz, 1H), 4.06 (dt, J = 12.1, 4.0 Hz, 2H),3.95 (d, J = 11.7 Hz, 2H), 3.85 (d, J = 11.7 Hz, 2H), 3.80-3.66 (m, 2H),3.44-3.37 (m, 3H), 2.22 (d, J = 13.1 Hz, 2H), 2.10 (d, J = 9.4 Hz, 1H),1.88-1.77 (m, 2H). 178 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.1Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.70 (s, 1H), 8.16-8.08 (m, 2H), 7.27(d, J = 5.1 Hz, 1H), 5.25 (q, J = 6.9 Hz, 1H), 4.82 (d, J = 7.1 Hz, 2H),3.99-3.78 (m, 4H), 2.10 (d, J = 9.5 Hz, 3H), 1.93 (d, J = 7.0 Hz, 6H),1.83-1.74 (m, 1H), 1.44-1.35 (m, 1H). 179 1H NMR (400 MHz, Methanol-d4)δ 8.79 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.61 (s, 1H), 8.08(d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.33-5.15(m, 3H), 4.85-4.76 (m, 3H), 3.98 (s, 4H), 3.79 (t, J = 5.1 Hz, 1H), 2.72(dd, J = 10.4, 6.0 Hz, 1H), 2.63 (d, J = 6.3 Hz, 2H), 2.05 (s, 3H), 1.70(dd, J = 10.3, 5.8 Hz, 1H). 180 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d,J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.62 (s, 1H), 8.14(s, 1H),8.11 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 5.22 (q, J = 7.1 Hz,1H), 3.83 (d, J = 12.9 Hz, 2H), 3.79-3.64 (m, 2H), 1.91 (d, J = 7.0 Hz,3H), 1.86-1.73 (m, 4H), 1.32 (s, 3H). 181 1H NMR (400 MHz, Methanol-d4)δ 8.78 (d, J = 2.2 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 7.96(d, J = 5.1 Hz, 1H), 7.66 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.02 (d, J= 6.7 Hz, 2H), 4.87 (d, J = 6.7 Hz, 2H), 3.83 (dt, J = 12.9, 4.1 Hz,2H), 3.74-3.64 (m, 2H), 1.94 (s, 3H), 1.86-1.72 (m, 4H), 1.32 (s, 3H).182 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J= 2.2 Hz, 1H), 8.50 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.88 (s, 1H),7.25 (d, J = 5.1 Hz, 1H), 4.38-4.21 (m, 2H), 4.19-4.07 (m, 2H), 4.01 (d,J = 13.3 Hz, 2H), 3.95-3.79 (m, 4H), 2.13 (s, 2H), 2.06 (s, 3H), 1.49(d, J = 6.4 Hz, 6H). 183 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J =2.2 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.51 (d, J = 9.0Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.25 (d, J = 5.0 Hz,1H), 5.32-5.17 (m, 3H), 4.80 (t, J = 6.0 Hz, 2H), 4.68-4.50 (m, 1H),4.46 (d, J = 10.6 Hz, 1H), 4.15 (d, J = 13.8 Hz, 1H), 3.81 (dd, J =29.4, 14.0 Hz, 1H), 3.63 (t, J = 11.7 Hz, 1H), 2.17-1.92 (m, 5H). 184 1HNMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.2Hz, 1H), 8.57 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 8.05 (d, J = 5.9 Hz,1H), 7.65 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.32-5.14 (m, 3H), 4.80 (t,J = 6.0 Hz, 2H), 4.01 (s, 1H), 3.84 (d, J = 11.8 Hz, 2H), 3.58 (d, J =11.9 Hz, 2H), 2.46 (s, 2H), 2.11-1.95 (m, 5H), 1.70 (d, J = 8.5 Hz, 2H).185 1H NMR (400 MHz, Methanol-d4) δ 8.80-8.76 (m, 2H), 8.70 (d, J = 2.2Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H), 8.05-7.99 (m, 2H), 7.98 (s, 1H), 7.78(d, J = 8.8 Hz, 2H), 7.26 (d, J = 5.0 Hz, 1H), 4.34 (hept, J = 6.4 Hz,1H), 2.19 (s, 3H), 1.55 (d, J = 6.4 Hz, 6H). 186 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.50(s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.0 Hz,1H), 4.53 (ddd, J = 47.1, 8.5, 4.2 Hz, 1H), 4.31 (p, J = 6.4 Hz, 1H),4.03 (td, J = 13.0, 4.2 Hz, 1H), 3.90-3.64 (m, 3H), 2.05-1.90 (m, 1H),1.82 (ddd, J = 14.1,9.6, 4.7 Hz, 1H), 1.49 (d, J = 6.4 Hz, 6H), 1.40 (d,J = 1.0 Hz, 3H). 187 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.07 (d, J = 5.0 Hz,1H), 7.65 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.31-5.17 (m, 3H), 4.80(dd, J = 6.6, 5.2 Hz, 2H), 3.88-3.79 (m, 2H), 3.77-3.63 (m, 2H),1.86-1.71 (m, 4H), 1.33 (s, 3H). 188 1H NMR (400 MHz, Methanol-d4) δ8.79 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.52 (s, 1H), 8.12(d, J = 5.1 Hz, 1H), 7.92 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.31 (dt, J= 9.8, 5.4 Hz, 1H), 4.05 (dt, J = 11.9, 4.1 Hz, 2H), 3.89-3.64 (m, 6H),2.20 (d, J = 13.1 Hz, 2H), 1.87-1.73 (m, 6H), 1.32 (s, 3H). 189 1H NMR(400 MHz, Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz,1H), 8.49 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J =5.0 Hz, 1H), 4.36-4.27 (m, 2H), 4.21 (s, 1H), 3.98-3.87 (m, 2H), 3.69(td, J = 12.7, 3.4 Hz, 2H), 1.88 (td, J = 13.0, 12.6, 4.9 Hz, 2H),1.81-1.71 (m, 2H), 1.49 (d, J = 6.4 Hz, 6H). 190 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.48(s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.88 (s, 1H), 7.25 (d, J = 5.1 Hz,1H), 4.53-4.33 (m, 1H), 4.33-4.25 (m, 1H), 4.13 (t, J = 13.3 Hz, 1H),3.99-3.81 (m, 2H), 3.68 (td, J = 12.8, 3.1 Hz, 1H), 2.04 (tt, J = 13.3,4.3 Hz, 1H), 1.68 (d, J = 14.0 Hz, 1H), 1.49 (d, J = 6.4 Hz, 6H), 1.35(s, 3H). 191 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H),8.70 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.88(s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.53-4.23 (m, 2H), 4.13 (t, J = 13.3Hz, 1H), 4.03-3.83 (m, 2H), 3.68 (td, J = 12.8, 3.1 Hz, 1H), 2.13-1.92(m, 1H), 1.68 (d, J = 14.1 Hz, 1H), 1.49 (d, J = 6.4 Hz, 6H), 1.35 (d, J= 2.2 Hz, 3H). 192 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz,1H), 8.70 (d, J = 2.2 Hz, 1H), 8.50 (s, 1H), 8.08 (d, J = 5.0 Hz, 1H),7.89 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.53 (ddd, J = 47.1, 8.5, 4.2Hz, 1H), 4.38-4.25 (m, 1H), 4.03 (td, J = 13.0, 4.2 Hz, 1H), 3.89-3.60(m, 3H), 2.05-1.90 (m, 1H), 1.88-1.76 (m, 1H), 1.49 (d, J = 6.4 Hz, 6H),1.40 (s, 3H). 193 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz,1H), 8.70 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H),7.88 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.38-4.18 (m, 3H), 4.08 (d, J =12.6 Hz, 2H), 3.95-3.80 (m, 5H), 2.08 (s, 3H), 2.05 (d, J = 7.4 Hz, 2H),1.49 (d, J = 6.4 Hz, 6H). 194 ¹H NMR (400 MHz, Methanol-d₄) δ 8.84-8.77(m, 2H), 8.72 (dd, J = 2.1, 1.2 Hz, 1H), 8.11 (dd, J = 5.1, 1.5 Hz, 1H),8.00 (d, J = 4.3 Hz, 1H), 7.26 (dd, J = 5.0, 1.1 Hz, 1H), 4.45-4.25 (m,1H), 4.12-3.84 (m, 1H), 2.59-2.33 (m, 2H), 2.33-2.17 (m, 2H), 2.15-1.68(m, 7H), 1.52 (dd, J = 6.4, 2.4 Hz, 6H). 194 Isomer 1 1H NMR (400 MHz,Methanol-d4) δ 8.83-8.75 (m, 2H), 8.72 (d, J = 2.1 Hz, 1H), 8.10 (d, J =5.0 Hz, 1H), 8.01 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.35 (hept, J = 6.3Hz, 1H), 4.09-3.99 (m, 1H), 2.51 (dddd, J = 23.6, 13.7, 9.2, 4.3 Hz,2H), 2.34-2.17 (m, 2H), 2.17-2.02 (m, 2H), 1.99 (s, 3H), 1.90 (dq, J =13.7, 7.1 Hz, 2H), 1.52 (d, J = 6.4 Hz, 6H). 194 Isomer 2 1H NMR (400MHz, Methanol-d4) δ 8.85-8.77 (m, 2H), 8.71 (d, J = 2.2 Hz, 1H), 8.10(d, J = 5.0 Hz, 1H), 8.00 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.34 (hept,J = 6.4 Hz, 1H), 3.98-3.80 (m, 1H), 2.53-2.20 (m, 4H), 2.12-1.94 (m,5H), 1.77 (qd, J = 12.5, 4.3 Hz, 2H), 1.51 (d, J = 6.4 Hz, 6H). 195 1HNMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.81 (d, J = 2.2 Hz, 1H),8.75 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.75 (s, 1H), 7.27(d, J = 5.1 Hz, 1H), 5.38-5.26 (m, 1H), 5.22 (q, J = 6.8, 6.1 Hz, 2H),4.83 (dd, J = 6.9, 5.6 Hz, 2H), 3.98-3.85 (m, 1H), 2.50-2.22 (m, 2H),2.04 (d, J = 14.2 Hz, 4H), 1.98 (s, 3H), 1.86-1.70 (m, 2H). 196 1H NMR(400 MHz, Methanol-d4) δ 8.88 (s, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.75(d, J = 2.1 Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.77 (s, 1H), 7.26 (d, J= 5.1 Hz, 1H), 5.38-5.26 (m, 1H), 5.26-5.19 (m, 2H), 4.82 (dd, J = 6.9,5.5 Hz, 2H), 4.09-3.99 (m, 1H), 2.53 (dddd, J = 23.8, 13.7, 9.2, 4.2 Hz,2H), 2.35-2.19 (m, 2H), 2.09 (ddd, J = 14.3, 9.3, 4.6 Hz, 2H), 2.00 (s,3H), 1.98-1.81 (m, 2H). 197 1H NMR (400 MHz, Methanol-d4) δ 8.81-8.78(m, 1H), 8.73 (s, 1H), 8.71 (d, J = 2.5 Hz, 1H), 8.12-8.08 (m, 1H), 7.98(s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.39-4.25 (m, 6H), 2.01 (s, 3H), 1.51(d, J = 5.9 Hz, 6H). 198 1H NMR (400 MHz, Methanol-d4) δ 8.82 (s, 1H),8.79 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 5.1 Hz,1H), 7.73 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 5.37-5.14 (m, 3H), 4.81(dd, J = 6.8, 5.5 Hz, 2H), 4.30 (s, 2H), 2.49 (t, J = 12.3 Hz, 2H),2.42-2.26 (m, 4H), 2.12 (t, J = 11.8 Hz, 2H), 1.94 (s, 3H). 199 1H NMR(400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.75-8.68 (m, 2H),8.09 (d, J = 5.1 Hz, 1H), 7.99 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H),4.38-4.25 (m, 1H), 3.80-3.63 (m, 1H), 2.69 (ddd, J = 9.4, 8.2, 2.6 Hz,2H), 2.62-2.47 (m, 2H), 1.54-1.46 (m, 9H). 200 1H NMR (400 MHz,Methanol-d4) δ 8.81-8.77 (m, 2H), 8.73 (d, J = 2.2 Hz, 1H), 8.08 (d, J =5.1 Hz, 1H), 7.75 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.32-5.15 (m, 3H),4.82 (dd, J = 6.6, 5.1 Hz, 2H), 3.84-3.64 (m, 1H), 2.70 (ddd, J = 9.4,8.2, 2.7 Hz, 2H), 2.61-2.50 (m, 2H), 1.52 (s, 3H). 201 1H NMR (400 MHz,Methanol-d4) δ 8.80 (d, J = 2.2 Hz, 1H), 8.77 (s, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.14 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.27 (d, J = 5.0 Hz,1H), 4.67 (t, J = 7.8 Hz, 1H), 4.34 (dt, J = 9.9, 5.4 Hz, 1H), 4.14-4.00(m, 3H), 3.80-3.69 (m, 2H), 2.87-2.76 (m, 2H), 2.74-2.60 (m, 2H), 2.22(d, J = 13.1 Hz, 2H), 1.98 (s, 3H), 1.93-1.78 (m, 2H). 202 1H NMR (400MHz, Methanol-d4) δ 8.83-8.78 (m, 2H), 8.74 (d, J = 2.1 Hz, 1H), 8.10(d, J = 5.1 Hz, 1H), 7.75 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.33-5.17(m, 3H), 4.84 (dd, J = 6.9, 5.6 Hz, 2H), 4.73-4.64 (m, 1H), 4.18-4.05(m, 1H), 2.90-2.76 (m, 2H), 2.70 (ddd, J = 12.9, 9.8, 7.6 Hz, 2H), 1.99(s, 3H). 203 1H NMR (400 MHz, Methanol-d4) δ 8.85-8.77 (m, 2H), 8.74 (d,J = 2.2 Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.74 (s, 1H), 7.26 (d, J =5.1 Hz, 1H), 5.38-5.26 (m, 1H), 5.23 (t, J = 6.8 Hz, 2H), 4.83 (dd, J =6.9, 5.5 Hz, 2H), 4.06-3.94 (m, 1H), 3.56-3.47 (m, 1H), 2.17 (ddd, J =24.5, 13.9, 8.0 Hz, 4H), 1.91-1.78 (m, 4H), 1.66 (td, J = 8.0, 4.1 Hz,1H), 0.86 (dt, J = 4.6, 3.1 Hz, 2H), 0.76 (dt, J = 8.1, 3.2 Hz, 2H). 2041H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J =2.2 Hz, 1H), 8.51 (s, 1H), 8.12 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.25(d, J = 5.1 Hz, 1H), 4.56-4.24 (m, 2H), 4.21-4.00 (m, 3H), 4.00-3.80 (m,2H), 3.80-3.61 (m, 3H), 2.20 (d, J = 13.1 Hz, 2H), 2.11-1.96 (m, 1H),1.86-1.61 (m, 3H), 1.35 (d, J = 2.2 Hz, 3H). 205 1H NMR (400 MHz,Methanol-d4) δ 8.84-8.78 (m, 2H), 8.74 (d, J = 2.2 Hz, 1H), 8.09 (d, J =5.0 Hz, 1H), 7.74 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.34-5.19 (m, 3H),4.83 (dd, J = 6.8, 5.4 Hz, 2H), 3.77 (t, J = 5.1 Hz, 1H), 3.66 (s, 3H),3.53-3.43 (m, 1H), 2.24-2.03 (m, 4H), 1.92-1.79 (m, 4H). 206 1H NMR (400MHz, Methanol-d4) δ 8.80-8.76 (m, 2H), 8.72 (d, J = 2.2 Hz, 1H), 8.07(d, J = 5.0 Hz, 1H), 7.78 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 5.30-5.19(m, 3H), 4.86-4.78 (m, 2H), 3.45-3.36 (m, 1H), 2.35-2.20 (m, 2H),1.99-1.78 (m, 4H), 1.78-1.64 (m, 2H), 1.31 (s, 3H). 207 1H NMR (400 MHz,Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.55(s, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.66 (s, 1H), 7.25 (d, J = 5.1 Hz,1H), 5.31-5.16 (m, 3H), 4.80 (dd, J = 6.7, 5.3 Hz, 2H), 4.42 (d, J =46.4 Hz, 1H), 4.16 (t, J = 13.1 Hz, 1H), 4.02-3.80 (m, 2H), 3.73-3.61(m, 1H), 2.05 (t, J = 13.6 Hz, 1H), 1.69 (d, J = 14.0 Hz, 1H), 1.35 (s,3H). 208 1H NMR (400 MHz, Methanol-d4) δ 8.80-8.76 (m, 2H), 8.72 (d, J =2.2 Hz, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.78 (s, 1H), 7.24 (d, J = 5.1Hz, 1H), 5.30-5.19 (m, 3H), 4.86-4.78 (m, 2H), 3.45-3.36 (m, 1H),2.35-2.20 (m, 2H), 1.99-1.78 (m, 4H), 1.78-1.64 (m, 2H), 1.31 (s, 3H).209 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J= 2.2 Hz, 1H), 8.51 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.90 (s, 1H),7.25 (d, J = 5.1 Hz, 1H), 5.25-5.10 (m, 1H), 4.40-4.24 (m, 1H), 4.16 (s,2H), 4.14-4.04 (m, 2H), 4.03-3.87 (m, 3H), 2.25 (dd, J = 13.3, 5.7 Hz,2H), 1.97-1.81 (m, 5H), 1.49 (d, J = 6.4 Hz, 6H). 210 1H NMR (400 MHz,Methanol-d4) δ 8.76 (s, 1H), 8.73 (s, 1H), 8.54 (s, 1H), 7.94 (d, J =5.0 Hz, 1H), 7.70 (s, 1H), 7.44 (d, J = 6.2 Hz, 1H), 7.24 (d, J = 5.0Hz, 1H), 5.04-5.00 (m, 2H), 4.86 (d, J = 6.7 Hz, 2H), 4.00 (d, J = 6.4Hz, 1H), 3.85 (d, J = 11.6 Hz, 2H), 3.58 (d, J = 12.2 Hz, 2H), 2.55-2.45(m, 2H), 2.07-1.97 (m, 2H), 1.94 (s, 3H), 1.75 (d, J = 8.8 Hz, 2H), 1.40(s, 6H). 211 1H NMR (400 MHz, Methanol-d4) δ 9.62 (s, 1H), 8.83 (s, 1H),8.78 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 5.0 Hz,1H), 8.02 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.35 (hept, J = 6.3 Hz,1H), 1.53 (d, J = 6.4 Hz, 6H). 212 1H NMR (400 MHz, Methanol-d4) δ8.82-8.63 (m, 3H), 8.07 (d, J = 5.3 Hz, 2H), 7.24 (d, J = 5.0 Hz, 1H),4.31 (p, J = 6.4 Hz, 1H), 3.66-3.55 (m, 4H), 1.50 (d, J = 6.4 Hz, 6H).213 1H NMR (400 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.72 (d, J = 2.1 Hz,1H), 8.66 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 8.03 (d, J = 5.0 Hz, 1H),7.21 (d, J = 5.0 Hz, 1H), 4.65 (dd, J = 9.8, 4.7 Hz, 1H), 4.55-4.47 (m,1H), 4.26 (p, J = 6.4 Hz, 1H), 2.58-2.47 (m, 2H), 2.40 (ddd, J = 12.8,8.3, 4.2 Hz, 2H), 1.50 (d, J = 6.4 Hz, 6H). 214 1H NMR (400 MHz,Methanol-d4) δ 8.85 (d, J = 1.2 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.72(d, J = 2.2 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.26 (d, J= 5.0 Hz, 1H), 4.36 (tdd, J = 14.5, 8.2, 4.5 Hz, 2H), 4.26 (dt, J =11.9, 7.2 Hz, 1H), 4.17 (ddd, J = 12.3, 7.5, 5.3 Hz, 1H), 3.89-3.70 (m,2H), 3.63 (dd, J = 11.1, 7.1 Hz, 0H), 2.31-1.90 (m, 4H), 1.53 (d, J =6.4 Hz, 6H). 215 1H NMR (400 MHz, Methanol-d4) δ 8.82 (s, 1H), 8.77 (d,J = 2.1 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H),8.01 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 4.33 (p, J = 6.4 Hz, 1H),4.14-4.01 (m, 2H), 2.77 (dtd, J = 9.7, 7.0, 3.1 Hz, 2H), 2.17-2.03 (m,2H), 1.50 (d, J = 6.4 Hz, 6H). 216 1H NMR (400 MHz, Methanol-d4) δ 8.86(d, J = 0.9 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H),8.13 (d, J = 5.1 Hz, 1H), 8.01 (s, 1H), 7.27 (d, J = 5.1 Hz, 1H),4.43-4.32 (m, 2H), 4.14 (dt, J = 12.0, 7.8 Hz, 1H), 4.00-3.83 (m, 2H),3.75-3.58 (m, 3H), 3.52 (dd, J = 12.8, 7.2 Hz, 1H), 2.58 (dp, J = 33.2,7.1 Hz, 1H), 2.32-2.10 (m, 1H), 1.89 (ddq, J = 44.3, 12.6, 8.2 Hz, 1H),1.53 (d, J = 6.4 Hz, 6H). 217 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J= 1.6 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.14(d, J = 5.1 Hz, 1H), 8.01 (s, 1H), 7.27 (d, J = 5.0 Hz, 1H), 4.44-4.30(m, 2H), 4.30-4.12 (m, 1H), 3.89-3.69 (m, 2H), 3.62 (dd, J = 11.1, 7.1Hz, 0H), 2.26-1.98 (m, 4H), 1.53 (d, J = 6.3 Hz, 6H). 218 1H NMR (400MHz, Methanol-d4) δ 8.83 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.71 (d, J =2.2 Hz, 1H), 8.09 (d, J = 5.0 Hz, 1H), 8.04 (s, 1H), 7.25 (d, J = 5.1Hz, 1H), 4.34 (hept, J = 6.3 Hz, 1H), 4.23-4.11 (m, 1H), 2.54 (ddd, J =10.1, 7.6, 2.8 Hz, 2H), 2.29 (dd, J = 11.7, 8.7 Hz, 2H), 1.52 (d, J =6.4 Hz, 6H), 1.42 (s, 3H). 219 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J =7.7 Hz, 1H), 9.13 (s, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.87 (s, 1H), 8.81(d, J = 2.2 Hz, 1H), 8.22 (s, 1H), 7.98 (d, J = 4.9 Hz, 1H), 7.19 (d, J= 4.9 Hz, 1H), 4.54 (p, J = 7.9 Hz, 1H), 4.08 (dt, J = 13.1, 6.5 Hz,1H), 2.33-2.16 (m, 4H), 1.39 (d, J = 6.3 Hz, 6H), 1.29 (s, 3H). 220 1HNMR (400 MHz, Methanol-d4) δ 8.80 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H),8.68 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.22(d, J = 5.0 Hz, 1H), 2.05 (d, J = 11.7 Hz, 4H), 1.65-1.51 (m, 2H), 1.50(d, J = 6.4 Hz, 6H), 1.48-1.36 (m, 2H). 221 1H NMR (400 MHz,Methanol-d4) δ 8.86 (s, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.13 (d, J = 5.0 Hz, 1H), 8.03 (s, 1H), 7.26 (d, J = 5.0 Hz,1H), 4.38 (ddt, J = 19.3, 12.9, 6.9 Hz, 2H), 4.14 (dt, J = 12.2, 7.7 Hz,1H), 4.01-3.80 (m, 2H), 3.76-3.58 (m, 3H), 3.55-3.48 (m, 1H), 2.68-2.48(m, 1H), 2.26-2.10 (m, 1H), 2.00-1.78 (m, 1H), 1.53 (d, J = 6.4 Hz, 6H).222 1H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J = 1.9 Hz, 1H), 8.79 (d, J= 2.1 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.02(d, J = 1.3 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.41-4.20 (m, 4H),4.12-4.03 (m, 1H), 3.92 (dd, J = 13.0, 6.2 Hz, 1H), 3.87-3.73 (m, 1H),3.63 (dd, J = 12.9, 4.5 Hz, 0H), 2.38-2.20 (m, 1H), 2.04 (ddq, J = 36.4,13.0, 6.4 Hz, 1H), 1.53 (d, J = 6.4 Hz, 6H), 1.48 (d, J = 3.9 Hz, 9H).223 1H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J = 1.8 Hz, 1H), 8.79 (d, J= 2.2 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 8.02(d, J = 1.2 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.43-4.20 (m, 4H), 4.08(d, J = 12.1 Hz, 1H), 3.92 (dd, J = 12.9, 6.2 Hz, 0H), 3.81 (qt, J =12.9, 7.1 Hz, 1H), 3.63 (dd, J = 13.0, 4.4 Hz, 0H), 2.28 (ddt, J = 33.8,13.4, 6.6 Hz, 1H), 2.04 (ddq, J = 32.8, 13.3, 6.4 Hz, 1H), 1.53 (d, J =6.4 Hz, 6H), 1.48 (d, J = 4.0 Hz, 10H). 224 1H NMR (400 MHz,Methanol-d4) δ 8.80 (s, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.2Hz, 1H), 8.15 (s, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.21 (d, J = 5.0 Hz,1H), 4.32-4.19 (m, 1H), 3.98 (t, J = 3.9 Hz, 2H), 1.99-1.66 (m, 8H),1.50 (d, J = 6.4 Hz, 6H). 225 1H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J= 1.8 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.11(d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.67 (d, J= 13.8 Hz, 1H), 4.37 (td, J = 12.9, 11.5, 5.0 Hz, 2H), 4.05 (s, 1H),3.89 (s, 0H), 3.71-3.59 (m, 2H), 3.21-3.13 (m, 1H), 2.11-1.89 (m, 1H),1.79-1.61 (m, 2H), 1.55-1.39 (m, 16H). 226 1H NMR (400 MHz, Methanol-d4)δ 8.86 (d, J = 4.9 Hz, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.11 (dd, J = 5.1, 1.4 Hz, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.26(d, J = 5.1 Hz, 1H), 4.50-4.29 (m, 2H), 4.20 (q, J = 6.9 Hz, 1H), 3.78(dq, J = 18.9, 9.6, 8.5 Hz, 1H), 3.56-3.36 (m, 1H), 3.21 (dd, J = 14.1,5.4 Hz, 0H), 2.26-1.93 (m, 5H), 1.53 (dd, J = 6.4, 2.1 Hz, 6H), 1.42 (d,J = 15.1 Hz, 9H). 227 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2Hz, 1H), 8.75 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 5.1 Hz,1H), 8.09-7.99 (m, 1H), 7.95 (s, 1H), 7.72 (s, 1H), 7.44 (t, J = 59.9Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.10 (s, 1H), 3.78 (s, 1H), 2.77 (s,1H), 2.43-2.26 (m, 4H), 2.23 (d, J = 10.5 Hz, 2H), 2.12 (d, J = 12.7 Hz,2H), 1.97 (s, 3H), 1.88-1.59 (m, 6H), 1.50 (q, J = 12.3 Hz, 1H). 228 1HNMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 5.0 Hz, 1H), 8.79 (d, J = 2.2Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 5.1, 1.4 Hz, 1H), 8.02(s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.47-4.31 (m, 2H), 4.20 (q, J = 7.1Hz, 1H), 3.78 (dq, J = 17.8, 9.5, 8.5 Hz, 1H), 3.55-3.37 (m, 1H), 3.21(dd, J = 14.1, 5.4 Hz, 0H), 2.31-1.90 (m, 5H), 1.53 (d, J = 6.4 Hz, 6H),1.42 (d, J = 14.7 Hz, 9H). 229 1H NMR (400 MHz, Methanol-d4) δ 8.84 (d,J = 5.6 Hz, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H),8.13 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.24 (d, J = 5.0 Hz, 1H), 4.61(dd, J = 8.4, 4.2 Hz, 1H), 4.42-4.18 (m, 3H), 3.29-3.20 (m, 1H),2.35-2.08 (m, 4H), 1.94 (dq, J = 11.1, 5.2, 4.7 Hz, 1H), 1.52 (d, J =6.4 Hz, 6H). 230 1H NMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.79 (d,J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H),8.06 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.62 (ddd, J = 12.4, 8.1, 4.7Hz, 1H), 4.42-4.30 (m, 2H), 4.29-4.18 (m, 1H), 3.31-3.17 (m, 2H), 2.20(dddd, J = 43.9, 18.0, 12.4, 6.4 Hz, 3H), 1.95 (td, J = 11.3, 5.4 Hz,1H), 1.53 (d, J = 6.4 Hz, 6H). 231 1H NMR (400 MHz, Methanol-d4) δ 8.78(d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.49 (s, 1H), 8.08 (d, J= 5.0 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.34 (s, 2H),4.33-4.25 (m, 1H), 4.23 (s, 3H), 2.71 (ddd, J = 10.5, 7.7, 3.0 Hz, 2H),2.39-2.23 (m, 2H), 1.94 (s, 3H), 1.48 (d, J = 6.4 Hz, 6H), 1.42-1.28 (m,1H). 232 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.69(d, J = 2.2 Hz, 1H), 8.52 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.90 (s,1H), 7.25 (d, J = 5.0 Hz, 1H), 4.31 (p, J = 6.4 Hz, 1H), 3.83 (t, J =5.4 Hz, 2H), 3.78 (s, 4H), 3.69 (dd, J = 6.6, 4.0 Hz, 2H), 2.20 (s, 3H),1.49 (d, J = 6.4 Hz, 6H). 233 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J= 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.09 (d, J = 5.1Hz, 1H), 7.91 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.82 (d, J = 6.7 Hz,2H), 4.32 (p, J = 6.4 Hz, 1H), 4.01-3.76 (m, 4H), 3.40 (dd, J = 16.4,7.3 Hz, 1H), 2.10 (d, J = 9.4 Hz, 1H), 1.50 (d, J = 6.4 Hz, 6H). 234 1HNMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2Hz, 1H), 8.53 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.92 (s, 1H), 7.25 (d,J = 5.0 Hz, 1H), 4.48 (dd, J = 24.4, 8.7 Hz, 4H), 4.39-4.24 (m, 1H),3.94 (d, J = 11.2 Hz, 2H), 3.05 (q, J = 7.0 Hz, 1H), 2.11 (d, J = 8.5Hz, 1H), 2.06 (s, 2H), 1.50 (d, J = 6.4 Hz, 6H). 235 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.50(s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.0 Hz,1H), 4.54 (s, 2H), 4.39-4.24 (m, 1H), 3.75-3.52 (m, 4H), 2.21-2.00 (m,2H), 1.95 (d, J = 7.2 Hz, 2H), 1.49 (d, J = 6.4 Hz, 6H). 236 1H NMR (400MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H),8.51 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.91 (s, 1H), 7.25 (d, J = 5.1Hz, 1H), 4.31 (d, J = 8.7 Hz, 3H), 3.94 (d, J = 11.3 Hz, 2H), 3.81-3.63(m, 2H), 2.19 (dd, J = 13.6, 2.2 Hz, 5H), 1.49 (d, J = 6.4 Hz, 6H). 2371H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J =2.2 Hz, 1H), 8.50 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.90 (s, 1H), 7.25(d, J = 5.1 Hz, 1H), 4.79 (d, J = 17.4 Hz, 2H), 4.31 (p, J = 6.4 Hz,1H), 4.03-3.86 (m, 2H), 3.80-3.62 (m, 1H), 3.59-3.47 (m, 1H), 2.24-2.04(m, 2H), 1.49 (d, J = 6.4 Hz, 6H), 1.42-1.27 (m, 2H). 238 1H NMR (400MHz, Methanol-d4) δ 8.78 (s, 1H), 8.70 (s, 1H), 8.51 (s, 1H), 8.09 (d, J= 5.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.83-4.67 (m,2H), 4.41-4.24 (m, 1H), 4.08-3.88 (m, 2H), 3.74 (d, J = 1.5 Hz, 1H),3.58-3.47 (m, 1H), 2.28-2.03 (m, 2H), 1.49 (d, J = 6.3 Hz, 6H), 1.31 (s,1H). 239 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70(d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.39 (s, 0H), 8.08 (d, J = 5.1 Hz,1H), 7.89 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.37-4.24 (m, 1H),3.91-3.75 (m, 4H), 2.53 (s, 1H), 2.01 (s, 2H), 1.96 (s, 3H), 1.48 (d, J= 6.4 Hz, 6H), 1.42 (dd, J = 23.4, 6.4 Hz, 1H). 240 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.50(s, 1H), 8.38 (s, 0H), 8.08 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.25 (d,J = 5.0 Hz, 1H), 4.36-4.23 (m, 1H), 3.94-3.74 (m, 4H), 2.53 (s, 1H),2.01 (s, 2H), 1.96 (s, 3H), 1.48 (d, J = 6.3 Hz, 6H). 241 1H NMR (400MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H),8.71 (s, 1H), 8.43 (s, 1H), 8.02 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 5.1Hz, 1H), 3.77 (tt, J = 11.6, 4.0 Hz, 1H), 3.27 (dt, J = 12.0, 3.6 Hz,1H), 2.60-2.21 (m, 7H), 2.17-1.97 (m, 6H), 1.97 (s, 3H), 1.95-1.70 (m,3H), 1.49 (qd, J = 12.9, 3.4 Hz, 2H). 242 1H NMR (400 MHz, Methanol-d4)δ 8.82 (s, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.07(d, J = 5.0 Hz, 1H), 8.03 (s, 1H), 7.22 (d, J = 5.1 Hz, 1H), 5.13-4.98(m, 1H), 4.75-4.59 (m, 1H), 4.55 (t, J = 9.7 Hz, 1H), 4.42-4.23 (m, 1H),4.13 (dd, J = 10.9, 5.6 Hz, 1H), 2.00 (s, 3H), 1.49 (d, J = 6.4 Hz, 6H).243 1H NMR (400 MHz, Methanol-d4) δ 10.00 (s, 1H), 9.96 (s, 1H), 9.94(s, 1H), 9.31 (d, J = 5.0 Hz, 1H), 9.05 (s, 1H), 8.47 (d, J = 5.0 Hz,1H), 5.40 (d, J = 7.3 Hz, 1H), 4.99 (s, 1H), 4.09 (t, J = 9.4 Hz, 2H),3.53 (q, J = 11.6, 10.2 Hz, 4H), 3.34 (d, J = 12.5 Hz, 2H), 3.19 (s,3H), 3.12-2.92 (m, 2H), 2.74 (s, 4H), 2.70 (s, 1H). 244 1H NMR (400 MHz,Methanol-d4) δ 10.00 (s, 1H), 9.96 (s, 1H), 9.94 (s, 1H), 9.31 (d, J =5.0 Hz, 1H), 9.05 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 5.49-5.31 (m, 1H),4.99 (s, 1H), 4.09 (t, J = 9.4 Hz, 2H), 3.53 (q, J = 11.6, 10.2 Hz, 5H),3.34 (d, J = 12.5 Hz, 2H), 3.19 (s, 3H), 3.14-2.95 (m, 2H), 2.74 (s,4H). 245 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.70(s, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.97 (s,1H), 7.23 (d, J = 5.1 Hz, 1H), 4.10 (s, 0H), 3.84 (d, J = 10.2 Hz, 1H),3.76 (d, J = 11.8 Hz, 1H), 3.47 (s, 0H), 2.41 (d, J = 12.4 Hz, 1H), 2.30(d, J = 13.1 Hz, 2H), 2.09 (d, J = 13.8 Hz, 3H), 1.98 (s, 1H), 1.94 (s,3H), 1.93 (s, 0H), 1.79 (q, J = 11.9 Hz, 2H), 1.61-1.36 (m, 4H). 246 1HNMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.77-8.66 (m,2H), 8.10 (d, J = 5.0 Hz, 1H), 7.98 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H),4.33 (hept, J = 6.4 Hz, 1H), 2.63 (s, 5H), 1.96 (s, 3H), 1.51 (d, J =6.4 Hz, 6H). 247 1H NMR (400 MHz, Methanol-d4) δ 9.39 (s, 0H), 8.80 (d,J = 2.1 Hz, 1H), 8.75-8.67 (m, 2H), 8.11 (dd, J = 5.1, 1.7 Hz, 1H), 7.97(s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.34 (p, J = 6.4 Hz, 1H), 3.93 (p, J= 8.1 Hz, 1H), 2.71 (dt, J = 12.5, 7.4 Hz, 0H), 2.43-2.27 (m, 1H),2.27-2.13 (m, 1H), 2.13-2.01 (m, 1H), 1.97 (d, J = 3.8 Hz, 3H),1.97-1.83 (m, 1H), 1.85-1.67 (m, 1H), 1.51 (d, J = 6.4 Hz, 6H). 248 1HNMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.2 Hz, 1H), 8.73 (s, 1H),8.71 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 7.97 (s, 1H), 7.26(d, J = 5.0 Hz, 1H), 4.45-4.26 (m, 2H), 3.96-3.73 (m, 1H), 2.71 (dt, J =14.1, 7.4 Hz, 1H), 2.42-2.28 (m, 1H), 2.27-2.01 (m, 2H), 1.97 (d, J =3.9 Hz, 3H), 1.96-1.86 (m, 1H), 1.85-1.71 (m, 0H), 1.54-1.40 (m, 6H).249 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J= 2.2 Hz, 1H), 8.49 (d, J = 0.8 Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.89(s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.31 (p, J = 6.4 Hz, 1H), 4.05-3.90(m, 1H), 3.92-3.73 (m, 1H), 3.65-3.53 (m, 1H), 2.03 (s, 3H), 1.98 (d, J= 10.8 Hz, 3H), 1.79 (td, J = 12.9, 12.5, 5.5 Hz, 1H), 1.60 (td, J =12.8, 5.3 Hz, 1H), 1.49 (d, J = 6.2 Hz, 7H). 250 1H NMR (400 MHz,Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.48(s, 1H), 8.05 (d, J = 5.0 Hz, 1H), 7.94 (s, 1H), 7.23 (d, J = 5.0 Hz,1H), 4.39-4.17 (m, 2H), 3.84-3.43 (m, 4H), 2.01 (s, 3H), 1.89 (d, J =3.8 Hz, 1H), 1.60 (d, J = 26.1 Hz, 1H), 1.48 (d, J = 6.4 Hz, 6H). 251 ¹HNMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 22 Hz, 1H), 8.67 (d, J = 2.2Hz, 1H), 8.49 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.91 (s, 1H), 7.22 (d,J = 5.1 Hz, 1H), 4.32-4.23 (m, 1H), 3.85-3.51 (m, 3H), 2.02 (s, 3H),1.47 (d, J = 6.4 Hz, 6H). 252 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J= 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 8.08 (d, J = 5.1Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.47 (s, 4H), 4.38-4.24(m, 1H), 1.48 (d, J = 6.4 Hz, 6H). 253 1H NMR (400 MHz, Methanol-d4) δ8.78 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.69 (s, 1H), 8.45(s, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.25 (d, J = 5.0 Hz, 1H), 3.65 (d, J= 6.7 Hz, 3H), 3.58-3.42 (m, 1H), 3.20-3.07 (m, 0H), 2.41-2.26 (m, 7H),2.26-2.04 (m, 2H), 2.04-1.89 (m, 6H), 1.74 (dq, J = 43.0, 14.0, 13.2 Hz,2H), 1.59-1.20 (m, 2H). 254 1H NMR (400 MHz, Methanol-d4) δ 8.74 (s,1H), 8.72 (s, 1H), 8.48 (s, 1H), 8.00 (d, J = 4.9 Hz, 1H), 7.88 (s, 1H),7.20 (d, J = 5.2 Hz, 1H), 4.52 (s, 2H), 4.08 (s, 1H), 3.74 (d, J = 29.8Hz, 1H), 3.69 (s, 3H), 3.53 (d, J = 41.9 Hz, 1H), 3.37 (d, J = 7.4 Hz,2H), 3.13 (s, 1H), 2.51 (s, 3H), 2.30 (s, 2H), 2.02 (s, 3H), 1.98 (s,1H), 1.29 (s, 1H). 255 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.2Hz, 1H), 8.78 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 5.0 Hz,1H), 8.02 (s, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.33 (dt, J = 10.1, 5.3 Hz,1H), 4.14-4.01 (m, 2H), 3.76 (q, J = 11.3, 10.3 Hz, 3H), 2.34 (d, J =12.9 Hz, 2H), 2.28-2.18 (m, 2H), 2.12 (d, J = 12.8 Hz, 2H), 1.97 (s,3H), 1.92-1.74 (m, 5H), 1.59-1.40 (m, 2H). 256 1H NMR (400 MHz,Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.54(s, 1H), 8.13 (d, J = 5.0 Hz, 1H), 7.93 (s, 1H), 7.25 (d, J = 5.1 Hz,1H), 4.54 (s, 2H), 4.37-4.25 (m, 1H), 4.11-4.00 (m, 2H), 3.79-3.70 (m,2H), 3.68 (d, J = 12.1 Hz, 2H), 3.60-3.55 (m, 2H), 2.20 (d, J = 13.1 Hz,2H), 2.14-2.02 (m, 2H), 1.95 (d, J = 7.4 Hz, 2H), 1.88-1.71 (m, 2H). 2571H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.70 (d, J =2.2 Hz, 1H), 8.53 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.91 (s, 1H), 7.25(d, J = 5.1 Hz, 1H), 4.36-4.28 (m, 1H), 4.24 (s, 4H), 3.37 (s, 4H), 1.49(d, J = 6.4 Hz, 6H). 258 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J =2.3 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.09 (d, J = 4.9Hz, 1H), 7.91 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.76 (s, 1H), 4.61 (s,1H), 4.37-4.26 (m, 1H), 4.17-4.04 (m, 2H), 3.92 (d, J = 11.6 Hz, 1H),3.80 (d, J = 10.6 Hz, 1H), 2.01 (s, 3H), 1.84 (d, J = 9.6 Hz, 1H), 1.50(d, J = 6.4 Hz, 6H), 1.38 (d, J = 6.2 Hz, 1H). 259 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.52(s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 5.0 Hz,1H), 4.82 (s, 1H), 4.55 (d, J = 6.7 Hz, 1H), 4.31 (p, J = 6.4 Hz, 1H),3.92 (d, J = 12.4 Hz, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.57 (t, J = 12.2Hz, 2H), 2.20 (s, 3H), 2.12-1.85 (m, 4H), 1.49 (d, J = 6.4 Hz, 6H) 2601H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J =2.1 Hz, 1H), 8.52 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.92 (s, 1H), 7.25(d, J = 5.0 Hz, 1H), 4.48 (d, J = 28.2 Hz, 3H), 4.38 (d, J = 13.3 Hz,1H), 4.35-4.26 (m, 1H), 3.83 (d, J = 12.7 Hz, 1H), 3.68 (d, J = 12.7 Hz,1H), 2.21 (s, 2H), 2.16 (s, 3H), 2.00 (d, J = 8.4 Hz, 1H), 1.88 (d, J =7.7 Hz, 1H), 1.49 (d, J = 6.4 Hz, 6H). 261 1H NMR (400 MHz, Methanol-d4)δ 8.77 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 8.07(d, J = 5.0 Hz, 1H), 7.93 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.76 (s,1H), 4.61 (s, 1H), 4.34-4.26 (m, 1H), 4.17-4.05 (m, 2H), 3.92 (d, J =11.4 Hz, 1H), 3.80 (d, J = 11.0 Hz, 1H), 2.92 (d, J = 8.5 Hz, 1H), 2.01(s, 3H), 1.84 (d, J = 9.3 Hz, 1H), 1.49 (d, J = 6.4 Hz, 6H), 1.43 (s,2H). 262 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70(d, J = 2.1 Hz, 1H), 8.54 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.92 (s,1H), 7.25 (d, J = 5.1 Hz, 1H), 4.28 (s, 2H), 4.14 (d, J = 6.6 Hz, 4H),4.01 (dd, J = 8.4, 3.2 Hz, 2H), 3.96 (d, J = 3.5 Hz, 1H), 1.49 (d, J =6.4 Hz, 6H). 263 ¹H NMR (400 MHz, Acetonitrile-6/3) δ 8.70-8.55 (m, 2H),8.50 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.73 (s, 1H), 7.20 (d, J = 5.1Hz, 1H), 4.73 (s, 3H), 4.31-4.13 (m, 1H), 3.94-3.76 (m, 1H), 3.77-3.63(m, 1H), 3.65-3.39 (m, 1H), 2.21-2.05 (m, 1H), 1.94-1.81 (m, 1H), 1.47(s, 1H), 1.45 (d, J = 6.4 Hz, 6H), 0.97-0.73 (m, 6H). 264 ¹H NMR (400MHz, Acetonitrile-6/3) δ 8.67 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.59(d, J = 2.2 Hz, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.51 (s, 1H), 7.19 (d, J= 5.1 Hz, 1H), 4.93 (d, J = 6.5 Hz, 2H), 4.78 (d, J = 6.7 Hz, 2H),4.76-4.72 (m, 1H), 4.39 (d, J = 6.8 Hz, 1H), 3.75 (dd, J = 27.4, 12.0Hz, 2H), 3.51 (dd, J = 18.3, 11.7 Hz, 2H), 2.69 (m, 4H), 2.10 (s, 3H),1.89 (s, 3H). 265 ¹H NMR (400 MHz, Methanol-6/4) δ 8.73 (d, J = 2.2 Hz,1H), 8.64 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H),7.54 (s, 1H), 7.20 (d, J = 5.0 Hz, 1H), 4.37-4.23 (m, 2H), 4.23-4.13 (m,2H), 4.15-4.03 (m, 3H), 3.93-3.85 (m, 1H), 3.84-3.75 (m, 2H), 3.76-3.65(m, 1H), 2.23 (s, 3H), 1.38 (d, J = 6.4 Hz, 6H). 266 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.51(d, J = 11.3 Hz, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 9.3 Hz,1H), 7.25 (d, J = 5.0 Hz, 1H), 4.69 (s, 1H), 4.30 (dd, J = 13.9, 7.8 Hz,2H), 4.22-4.02 (m, 5H), 3.93-3.66 (m, 4H), 2.21 (d, J = 14.4 Hz, 3H),1.49 (d, J = 6.4 Hz, 6H). 267 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J= 2.1 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.57 (s, 1H), 8.09 (d, J = 5.1Hz, 1H), 7.91 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.39-4.26 (m, 2H), 3.75(dt, J = 12.1, 4.1 Hz, 1H), 3.69-3.57 (m, 1H), 3.45 (td, J = 6.9, 4.6Hz, 1H), 3.33-3.22 (m, 2H), 2.28 (s, 3H), 2.20 (s, 1H), 1.52-1.48 (m,6H), 1.48-1.35 (m, 1H), 1.00-0.91 (m, 1H). 268 1H NMR (400 MHz,Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.77 (s, 1H), 8.75 (d, J = 2.2Hz, 1H), 8.38 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 5.1 Hz,1H), 3.94-3.71 (m, 5H), 3.34-3.25 (m, 1H), 2.33 (d, J = 14.0 Hz, 4H),2.17-2.01 (m, 4H), 1.97 (s, 3H), 1.84 (td, J = 12.7, 3.2 Hz, 2H), 1.78(s, 3H), 1.50 (qd, J = 12.8, 3.4 Hz, 2H). 269 1H NMR (400 MHz,Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.53(s, 1H), 8.13 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.25 (d, J = 5.0 Hz,1H), 4.69 (s, 1H), 4.33-4.17 (m, 4H), 4.14-4.01 (m, 4H), 3.89 (d, J =11.9 Hz, 1H), 3.82 (d, J = 10.0 Hz, 2H), 3.79-3.68 (m, 4H), 2.23 (s,3H), 2.19 (s, 2H), 1.88-1.74 (m, 2H). 270 1H NMR (400 MHz, Methanol-d4)δ 8.79 (d, J = 2.1 Hz, 1H), 8.77 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.13(d, J = 5.1 Hz, 1H), 8.03 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.33 (tt, J= 9.4, 4.2 Hz, 1H), 4.06 (dt, J = 12.0, 4.0 Hz, 2H), 3.74 (ddd, J =12.1, 10.3, 2.5 Hz, 2H), 2.64 (s, 6H), 2.21 (d, J = 12.9 Hz, 2H), 1.96(s, 3H), 1.90-1.75 (m, 2H), 0.12 (s, 0H). 271 1H NMR (400 MHz,Chloroform-d) δ 8.68 (d, J = 7.1 Hz, 1H), 8.53 (s, 1H), 8.34 (d, J = 2.3Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.91 (d, J = 4.8 Hz,1H), 7.00 (d, J = 4.8 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 4.22 (s, 2H),3.98 (h, J = 6.5 Hz, 1H), 3.66-3.56 (m, 2H), 2.76 (dt, J = 8.9, 6.5 Hz,1H), 1.60 (d, J = 9.1 Hz, 1H), 1.42 (d, J = 4.8 Hz, 16H). 272 ¹H NMR(400 MHz, Methanol-d₄) δ 8.78 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.2 Hz,1H), 8.52 (s, 1H), 8.27 (s, 1H), 8.06-8.01 (m, 1H), 7.98 (d, J = 5.1 Hz,1H), 7.25 (d, J = 5.1 Hz, 1H), 4.01 (d, J = 4.9 Hz, 1H), 3.92-3.74 (m,6H), 3.57 (d, J = 11.8 Hz, 2H), 2.46 (s, 2H), 2.30 (d, J = 14.2 Hz, 2H),2.05 (td, J = 9.5, 9.1, 4.4 Hz, 4H), 2.00 (s, 3H), 1.76 (s, 3H), 1.70(d, J = 8.3 Hz, 2H). 273 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J =2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.09 (d, J = 5.0Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 5.13 (s, 1H), 4.61 (s,1H), 4.37-4.19 (m, 2H), 4.19-4.09 (m, 1H), 3.95-3.86 (m, 1H), 3.87-3.78(m, 1H), 2.99-2.85 (m, 1H), 1.82 (d, J = 9.3 Hz, 1H), 1.50 (d, J = 6.4Hz, 6H), 1.46 (s, 3H), 1.31 (s, 3H). 274 1H NMR (400 MHz, Methanol-d4) δ8.73 (d, J = 6.9 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.1 Hz,1H), 8.44 (s, 1H), 8.25 (s, 1H), 7.82 (d, J = 4.9 Hz, 1H), 7.09 (d, J =5.0 Hz, 1H), 4.09-3.87 (m, 7H), 2.94 (s, 1H), 1.88 (d, J = 9.4 Hz, 1H),1.43 (d, J = 6.3 Hz, 7H). 275 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J= 2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.09 (d, J = 5.1Hz, 1H), 7.90 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 5.13 (s, 1H), 4.61 (s,1H), 4.38-4.21 (m, 2H), 4.14 (d, J = 10.6 Hz, 1H), 3.90 (d, J = 11.0Hz,1H), 3.82 (d, J = 11.0Hz, 1H), 3.02-2.83 (m, 1H), 1.82 (d, J = 9.2 Hz,1H), 1.50 (d, J = 6.4 Hz, 6H), 1.46 (s, 3H), 1.31 (s, 3H). 276 1H NMR(400 MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz,1H), 8.56 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J =5.1 Hz, 1H), 4.93 (s, 1H), 4.67 (s, 1H), 4.40-4.30 (m, 1H), 4.30-4.09(m, 2H), 4.04-3.73 (m, 4H), 3.35 (s, 6H), 3.06-2.91 (m, 1H), 1.87 (d, J= 9.3 Hz, 1H), 1.49 (d, J = 6.4 Hz, 6H). 277 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.56(s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.91 (s, 1H), 7.25 (d, J = 5.0 Hz,1H), 4.51 (d, J = 6.4 Hz, 2H), 4.33 (q, J = 6.3 Hz, 1H), 4.26 (d, J =11.2 Hz, 2H), 3.75 (d, J = 11.3 Hz, 2H), 2.96-2.95 (m, 6H), 2.94-2.86(m, 1H), 1.77 (d, J = 9.3 Hz, 1H), 1.49 (d, J = 6.4 Hz, 6H). 278 1H NMR(400 MHz, Methanol-d4) δ 8.81-8.55 (m, 3H), 8.10-7.93 (m, 2H), 7.20 (d,J = 5.0 Hz, 1H), 4.68-4.55 (m, 1H), 4.23 (q, J = 6.4 Hz, 1H), 4.02 (tt,J = 9.1, 4.6 Hz, 1H), 2.79 (ddd, J = 10.7, 9.2, 4.2 Hz, 2H), 2.66 (td, J= 12.4, 11.0, 8.1 Hz, 2H), 1.95 (s, 3H), 1.49 (d, J = 6.4 Hz, 6H). 2791H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.73-8.62 (m,2H), 8.08 (d, J = 5.0 Hz, 1H), 7.95 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H),4.49-4.23 (m, 2H), 3.89-3.72 (m, 1H), 3.03-2.83 (m, 2H), 2.44 (qd, J =9.4, 2.7 Hz, 2H), 1.94 (s, 3H), 1.49 (d, J = 6.4 Hz, 6H). 280 1H NMR(400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.74-8.58 (m, 2H),8.07 (d, J = 5.0 Hz, 1H), 7.94 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.30(h, J = 6.5 Hz, 1H), 2.27-2.16 (m, 6H), 2.16-2.06 (m, 6H), 1.89 (s, 3H),1.48 (d, J = 6.4 Hz, 6H). 281 1H NMR (400 MHz, Methanol-d4) δ 8.68 (s,1H), 8.57 (t, J = 1.9 Hz, 2H), 8.05-7.91 (m, 2H), 7.17 (d, J = 5.1 Hz,1H), 4.64 (p, J = 8.0 Hz, 1H), 4.18 (p, J = 6.5 Hz, 1H), 4.02 (dt, J =9.5, 4.8 Hz, 1H), 2.78 (ddd, J = 12.6, 7.6, 4.0 Hz, 2H), 2.67 (td, J =12.8, 11.2, 8.3 Hz, 2H), 1.49 (d, J = 6.4 Hz, 7H), 0.87 (p, J = 4.2 Hz,2H), 0.74 (dq, J = 7.4, 4.3, 3.9 Hz, 2H). 282 1H NMR (400 MHz,Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.73-8.62 (m, 2H), 8.09 (d, J =5.1 Hz, 1H), 7.89 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.62 (q, J = 7.3,6.8 Hz, 1H), 4.18-3.95 (m, 1H), 3.34 (s, 3H), 2.87-2.74 (m, 2H),2.73-2.59 (m, 2H), 1.96 (s, 3H). 283 1H NMR (400 MHz, Methanol-d4) δ8.76 (d, J = 2.2 Hz, 1H), 8.72 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.07(d, J = 5.1 Hz, 1H), 7.99 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.93 (t, J= 7.5 Hz, 2H), 4.68 (dd, J = 8.0, 5.2 Hz, 2H), 4.44 (h, J = 6.1, 5.6 Hz,1H), 4.31 (p, J = 6.6 Hz, 1H), 4.23 (q, J = 6.9 Hz, 1H), 4.20-4.09 (m,1H), 2.89 (t, J = 7.5 Hz, 4H), 1.48 (d, J = 6.4 Hz, 6H). 284 1H NMR (400MHz, Methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.71 (s, 1H), 8.68 (d, J =2.1 Hz, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.94 (s, 1H), 7.23 (d, J = 5.1Hz, 1H), 4.31 (p, J = 6.3 Hz, 1H), 2.36-2.03 (m, 8H), 1.94 (s, 5H), 1.49(d, J = 6.4 Hz, 6H). 285 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J =2.2 Hz, 1H), 8.71 (d, J = 2.7 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.07(d, J = 5.0 Hz, 1H), 7.95 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.31 (p, J= 6.4 Hz, 1H), 3.85-3.66 (m, 2H), 2.74 (s, 1H), 2.54-2.33 (m, 1H),2.34-1.99 (m, 1H), 1.92 (d, J = 8.9 Hz, 3H), 1.82-1.56 (m, 3H), 1.49(dd, J = 6.4, 3.7 Hz, 6H), 1.37-1.22 (m, 1H), 1.19 (s, 1H). 286 1H NMR(400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.1 Hz,1H), 8.47 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.22 (d, J =5.0 Hz, 1H), 4.28 (p, J = 6.4 Hz, 1H), 4.21-4.06 (m, 4H), 1.59 (s, 3H),1.46 (d, J = 6.4 Hz, 6H). 287 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J= 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.05 (d, J = 5.1Hz, 1H), 7.86 (s, 1H), 7.22 (d, J = 5.0 Hz, 1H), 4.28 (p, J = 6.4 Hz,1H), 3.79 (d, J = 13.1 Hz, 2H), 3.75-3.51 (m, 2H), 1.85-1.63 (m, 4H),1.46 (d, J = 6.4 Hz, 6H), 1.30 (s, 3H). 288 1H NMR (400 MHz,Methanol-d4) δ 8.73 (d, J = 2.2 Hz, 1H), 8.70 (s, 1H), 8.66 (d, J = 2.2Hz, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.96 (s, 1H), 7.21 (d, J = 5.1 Hz,1H), 4.27 (q, J = 6.4 Hz, 1H), 2.50 (d, J = 3.6 Hz, 2H), 2.21 (dd, J =8.3, 4.3 Hz, 2H), 2.16-2.01 (m, 4H), 1.95 (s, 3H), 1.48 (d, J = 6.4 Hz,6H). 289 1H NMR (400 MHz, Methanol-d4) δ 7.21 (d, J = 5.0 Hz, 1H), 4.29(p, J = 6.4 Hz, 1H), 4.07-3.87 (m, 1H), 3.27 (d, J = 5.9 Hz, 2H),2.77-2.57 (m, 3H), 2.18 (td, J = 9.4, 8.9, 6.8 Hz, 2H), 1.96 (s, 3H),1.48 (d, J = 6.4 Hz, 6H). 290 1H NMR (400 MHz, Methanol-d4) δ 8.75 (s,1H), 8.72 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.08 (d, J =5.1 Hz, 1H), 7.96 (s, 1H), 7.20 (d, J = 5.0 Hz, 1H), 4.38-4.24 (m, 1H),4.18-4.00 (m, 1H), 3.39 (d, J = 7.3 Hz, 2H), 2.71 (tt, J = 8.5, 4.1 Hz,1H), 2.56 (ddd, J = 11.7, 8.7, 6.6 Hz, 2H), 2.42 (dtd, J = 12.7, 5.5,2.1 Hz, 2H), 1.97 (s, 3H), 1.48 (d, J = 6.4 Hz, 6H). 291 1H NMR (400MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H),8.46 (s, 1H), 8.05 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.22 (d, J = 5.1Hz, 1H), 4.27 (p, J = 6.4 Hz, 1H), 3.70 (d, J = 11.7 Hz, 2H), 3.41 (d, J= 11.7 Hz, 2H), 2.43 (s, 2H), 1.88-1.80 (m, 2H), 1.80-1.69 (m, 2H), 1.66(d, J = 7.9 Hz, 2H), 1.46 (d, J = 6.4 Hz, 6H). 292 1H NMR (400 MHz,Methanol-d4) δ 8.77 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.48(s, 1H), 8.09 (d, J = 4.9 Hz, 1H), 7.85 (s, 1H), 7.24 (d, J = 5.0 Hz,1H), 4.00 (s, 1H), 3.82 (d, J = 12.2 Hz, 1H), 3.55 (d, J = 12.0 Hz, 2H),2.45 (s, 2H), 2.03 (d, J = 22.7 Hz, 11H). 293 1H NMR (400 MHz,Methanol-d4) δ 8.74 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.46(s, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.22 (d, J = 5.1 Hz,1H), 4.58 (t, J = 7.5 Hz, 2H), 4.49 (d, J = 9.8 Hz, 2H), 4.40 (d, J =10.3 Hz, 2H), 4.27 (p, J = 6.2 Hz, 1H), 2.99 (t, J = 7.5 Hz, 2H), 1.45(d, J = 6.4 Hz, 6H). 294 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J =2.2 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 5.1Hz, 1H), 7.87 (s, 1H), 7.22 (d, J = 5.0 Hz, 1H), 4.28 (p, J = 6.4 Hz,1H), 3.83 (t, J = 5.9 Hz, 4H), 2.20 (tt, J = 13.0, 5.9 Hz, 4H), 1.46 (d,J = 6.4 Hz, 6H). 295 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.51 (s, 1H), 8.09 (d, J = 5.0 Hz,1H), 7.88 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.31 (p, J = 6.4 Hz, 1H),3.94 (d, J = 12.5 Hz, 2H), 3.63 (dd, J = 12.5, 3.8 Hz, 2H), 2.13 (s,2H), 1.99-1.74 (m, 8H), 1.49 (d, J = 6.4 Hz, 6H). 296 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.49(s, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.1 Hz,1H), 4.35-4.24 (m, 1H), 3.96 (dd, J = 37.0, 12.3 Hz, 2H), 3.55- 3.49 (m,1H), 2.03 (s, 1H), 1.99 (s, 3H), 1.85 (d, J = 26.8 Hz, 1H), 1.67 (d, J =10.8 Hz, 1H), 1.48 (d, J = 6.4 Hz, 6H). several aliphatic peaks obscuredby solvent 297 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H),8.66 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 8.05 (d, J = 5.0 Hz, 1H), 7.90(s, 1H), 7.22 (d, J = 5.1 Hz, 1H), 4.52 (d, J = 9.8 Hz, 2H), 4.31-4.23(m, 3H), 1.46 (d, J = 6.4 Hz, 6H). 298 1H NMR (400 MHz, Methanol-d4) δ8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.50 (s, 1H), 8.09(d, J = 5.1 Hz, 1H), 7.88 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.31 (p, J= 6.3 Hz, 1H), 3.93-3.81 (m, 3H), 3.79-3.60 (m, 2H), 2.20 (d, J = 14.1Hz, 1H), 2.06 (d, J = 7.0 Hz, 0H), 1.94 (s, 6H), 1.92-1.81 (m, 1H),1.70-1.56 (m, 1H), 1.49 (d, J = 6.4 Hz, 6H). 299 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.49(s, 1H), 8.21 (d, J = 6.8 Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.89 (s,1H), 7.25 (d, J = 5.1 Hz, 1H), 4.30 (p, J = 6.4 Hz, 1H), 3.95 (dd, J =37.3, 12.2 Hz, 2H), 3.55-3.43 (m, 1H), 1.99 (s, 4H), 1.80 (dd, J = 13.7,3.9 Hz, 1H), 1.67 (d, J = 10.9 Hz, 1H), 1.48 (d, J = 6.4 Hz, 6H).several aliphatic peaks obscured by solvent 300 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.50(s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.24 (d, J = 5.0 Hz,1H), 4.29 (dd, J = 13.1, 6.7 Hz, 2H), 3.85 (d, J = 11.6 Hz, 2H), 3.63(d, J = 11.6 Hz, 2H), 3.07 (s, 3H), 2.66 (s, 2H), 2.18 (s, 3H), 2.02 (s,2H), 1.81 (s, 2H), 1.49 (d, J = 6.4 Hz, 6H). 301 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.50(s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J = 5.1 Hz,1H), 4.42-4.34 (m, 2H), 4.34-4.26 (m, 1H), 3.91-3.82 (m, 3H), 3.74-3.68(m, 2H), 3.58 (d, J = 12.1 Hz, 2H), 2.86 (s, 2H), 2.03 (d, J = 10.4 Hz,2H), 1.77 (d, J = 8.2 Hz, 2H), 1.49 (d, J = 6.3 Hz, 6H). 302 1H NMR (400MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H),8.51 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.89 (s, 1H), 7.25(d, J = 5.0 Hz, 1H), 4.88 (s, 1H), 4.31 (p, J = 6.4 Hz, 1H), 3.84 (ddd,J = 24.2, 9.5, 2.0 Hz, 1H), 3.77 (d, J = 2.1 Hz, 1H), 3.69-3.51 (m, 2H),2.32-2.09 (m, 4H), 2.02 (s, 2H), 1.49 (d, J = 6.4 Hz, 6H). 303 1H NMR(400 MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.2 Hz,1H), 8.51 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H),7.25 (d, J = 5.1 Hz, 1H), 4.88 (s, 1H), 4.31 (p, J = 6.4 Hz, 1H), 3.84(ddd, J = 24.2, 9.5, 2.0 Hz, 1H), 3.77 (d, J = 2.1 Hz, 1H), 3.59 (ddd, J= 27.3, 17.4, 9.2 Hz, 2H), 2.33-2.08 (m, 4H), 2.02 (s, 2H), 1.49 (d, J =6.4 Hz, 6H). 304 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz,1H), 8.67 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H),7.87 (s, 1H), 7.22 (d, J = 5.1 Hz, 1H), 4.79 (t, J = 6.9 Hz, 2H), 4.70(t, J = 6.3 Hz, 2H), 4.29 (p, J = 6.5 Hz, 1H), 3.86 (t, J = 6.2 Hz, 1H),3.80 (t, J = 5.2 Hz, 4H), 2.82 (t, J = 5.2 Hz, 4H), 1.46 (d, J = 6.4 Hz,6H). 305 1H NMR (400 MHz, Methanol-d4) δ 8.74 (s, 1H), 8.66 (d, J = 2.1Hz, 1H), 8.46 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.88 (s, 1H), 7.21 (d,J = 4.9 Hz, 1H), 4.31-4.20 (m, 1H), 4.08 (d, J = 13.2 Hz, 2H), 3.37 (d,J = 14.7 Hz, 4H), 2.74 (d, J = 4.4 Hz, 3H), 1.89 (d, J = 13.8 Hz, 3H),1.46 (d, J = 6.4 Hz, 6H). 306 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J= 2.2 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.08 (d, J = 5.1Hz, 1H), 7.82 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.55 (d, J = 22.7 Hz,1H), 4.38 (d, J = 15.2 Hz, 1H), 4.09 (d, J = 14.0 Hz, 1H), 3.76 (dd, J =29.3, 14.0 Hz, 1H), 3.58 (t, J = 12.5 Hz, 1H), 2.01 (s, 4H). Severalpeaks obscured by solvent 307 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J= 2.1 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.43 (d, J = 8.8Hz, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.82 (s, 1H), 7.23 (d, J = 5.0 Hz,1H), 4.39 (s, 1H), 4.10 (d, J = 13.3 Hz, 1H), 3.76 (dd, J = 29.2, 14.2Hz, 1H), 3.58 (s, 1H), 2.01 (s, 3H). Several peaks obscured by solvent308 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.67 (d, J= 2.2 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J = 4.9 Hz, 2H), 8.05 (d, J = 5.1Hz, 1H), 7.86 (s, 1H), 7.22 (d, J = 5.1 Hz, 1H), 6.69 (t, J = 4.9 Hz,1H), 4.28 (p, J = 6.3 Hz, 1H), 4.10 (s, 1H), 3.85 (dd, J = 12.3, 3.1 Hz,2H), 3.61 (d, J = 12.0 Hz, 2H), 2.57 (s, 2H), 2.14-2.03 (m, 2H), 1.72(t, J = 7.4 Hz, 2H), 1.47 (d, J = 6.4 Hz, 6H). 309 1H NMR (400 MHz,Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.48(s, 1H), 8.05 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.84 (d, J = 5.3 Hz,1H), 7.39-7.29 (m, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.69-6.60 (m, 1H),4.29 (p, J = 6.2 Hz, 1H), 4.12 (s, 1H), 3.89-3.80 (m, 2H), 3.65 (d, J =12.0 Hz, 2H), 2.62 (s, 2H), 2.10 (d, J = 10.0 Hz, 2H), 1.71 (d, J = 8.4Hz, 2H), 1.47 (d, J = 6.4 Hz, 6H). 310 1H NMR (400 MHz, Methanol-d4) δ8.75 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.47 (s, 1H), 8.05(d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.22 (d, J = 5.0 Hz, 1H), 4.28 (p, J= 6.4 Hz, 1H), 3.92-3.84 (m, 2H), 3.69-3.56 (m, 2H), 2.13 (t, J = 10.0Hz, 3H), 2.07-1.90 (m, 2H), 1.46 (d, J = 6.4 Hz, 6H). 311 1H NMR (400MHz, Methanol-d4) δ 8.81 (s, 1H), 8.80 (s, 1H), 8.74 (d, J = 2.1 Hz,1H), 8.09 (d, J = 5.1 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H),7.26 (d, J = 5.1 Hz, 1H), 5.32-5.25 (m, 1H), 5.22 (t, J = 6.7 Hz, 2H),4.83 (dd, J = 6.9, 5.4 Hz, 2H), 3.97 (s, 1H), 3.54 (t, J = 6.0 Hz, 1H),2.17 (d, J = 6.7 Hz, 5H), 1.88 (p, J = 6.0, 5.5 Hz, 4H), 1.38 (s, 6H).312 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 2.1 Hz, 1H), 8.75 (s,1H), 8.71 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 7.98 (s, 1H),7.60 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 4.35 (p, J = 6.4 Hz,1H), 3.97 (d, J = 5.8 Hz, 1H), 3.56-3.47 (m, 1H), 2.15 (d, J = 6.7 Hz,4H), 1.87 (p, J = 6.3, 5.7 Hz, 4H), 1.52 (d, J = 6.4 Hz, 6H), 1.38 (s,6H). 313 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.71(s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.95 (s,1H), 7.23 (d, J = 5.1 Hz, 1H), 6.81 (s, 1H), 4.31 (p, J = 6.4 Hz, 1H),4.05 (s, 1H), 2.90 (d, J = 18.0 Hz, 1H), 2.71 (t, J = 19.3 Hz, 2H),2.33-2.18 (m, 1H), 2.08 (d, J = 12.8 Hz, 1H), 1.96 (s, 3H), 1.86-1.71(m, 1H), 1.49 (d, J = 6.4 Hz, 6H). 314 1H NMR (400 MHz, Methanol-d4) δ8.79 (d, J = 2.2 Hz, 1H), 8.74 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.10(d, J = 5.1 Hz, 1H), 7.97 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.26 (d, J= 5.1 Hz, 1H), 4.42 (d, J = 6.1 Hz, 2H), 4.34 (p, J = 6.4 Hz, 1H),3.93-3.77 (m, 1H), 2.35 (d, J = 13.0 Hz, 2H), 2.12 (d, J = 12.6 Hz, 2H),1.84 (qd, J = 13.1, 3.4 Hz, 3H), 1.62 (s, 3H), 1.51 (d, J = 6.4 Hz, 8H).Additional peak obscured by solvent. 315 1H NMR (400 MHz, Methanol-d4) δ8.79 (d, J = 2.1 Hz, 1H), 8.74 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.10(d, J = 5.0 Hz, 1H), 7.97 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.34 (p, J= 6.4 Hz, 1H), 3.85-3.71 (m, 1H), 3.36 (q, J = 3.4 Hz, 0H), 2.34 (d, J =13.0 Hz, 2H), 2.15-2.03 (m, 2H), 1.84 (qd, J = 12.9, 3.3 Hz, 2H), 1.59(qd, J = 12.9, 3.7 Hz, 2H), 1.51 (d, J = 6.4 Hz, 6H), 1.39 (s, 6H).Peakobscured by solvent. 316 1H NMR (400 MHz, Methanol-d4) δ 8.83 (s, 1H),8.73 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.23 (s, 1H), 8.08(d, J = 5.0 Hz, 1H), 7.22 (d, J = 5.1 Hz, 1H), 5.20 (q, J = 6.9 Hz, 1H),3.75 (ddq, J = 12.1, 7.8, 4.2 Hz, 1H), 2.31 (d, J = 13.2 Hz, 1H), 2.09(d, J = 12.3 Hz, 2H), 1.94 (s, 3H), 1.91 (d, J = 6.9 Hz, 3H), 1.80 (qd,J = 12.7, 2.4 Hz, 3H), 1.47 (qd, J = 12.9, 12.4, 2.9 Hz, 3H). 317 1H NMR(400 MHz, Methanol-d4) δ 8.81-8.62 (m, 3H), 8.07 (d, J = 5.1 Hz, 1H),7.95 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.31 (hept, J = 6.3 Hz, 1H),3.33 (d, J = 6.0 Hz, 2H), 2.12-1.97 (m, 2H), 1.49 (d, J = 6.4 Hz, 6H).318 1H NMR (400 MHz, Chloroform-d) δ 10.02 (d, J = 7.2 Hz, 1H), 9.24 (s,1H), 8.50-8.35 (m, 3H), 8.32 (d, J = 2.2 Hz, 1H), 7.11 (d, J = 5.1 Hz,1H), 4.30 (q, J = 7.1 Hz, 2H), 4.23 (s, 2H), 4.09 (h, J = 6.6 Hz, 1H),1.51 (d, J = 6.4 Hz, 6H), 1.34 (t, J = 7.2 Hz, 3H). 319 1H NMR (400 MHz,Methanol-d4) δ 9.58 (s, 1H), 8.87-8.74 (m, 2H), 8.68 (d, J = 2.1 Hz,1H), 8.13-7.92 (m, 2H), 7.22 (d, J = 5.1 Hz, 1H), 4.42-4.25 (m, 1H),2.99 (s, 1H), 2.86 (d, J = 0.8 Hz, 1H), 1.49 (dd, J = 6.4, 4.8 Hz, 6H).320 1H NMR (400 MHz, Methanol-d4) δ 8.82-8.74 (m, 2H), 8.68 (d, J = 2.2Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.23 (d, J= 5.0 Hz, 1H), 4.38-4.25 (m, 1H), 3.34 (s, 2H), 1.73 (s, 1H), 1.49 (dd,J = 6.5, 2.4 Hz, 6H), 1.31 (s, 5H). 321 1H NMR (400 MHz, Methanol-d4) δ8.81-8.73 (m, 2H), 8.68 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 5.0 Hz, 1H),7.99 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.63 (d, J = 5.7 Hz, 2H), 4.32(h, J = 6.4 Hz, 1H), 1.49 (d, J = 6.4 Hz, 6H). 322 1H NMR (400 MHz,Methanol-d4) δ 8.82-8.61 (m, 3H), 8.07 (d, J = 5.1 Hz, 1H), 7.95 (s,1H), 7.23 (d, J = 5.1 Hz, 1H), 4.31 (hept, J = 6.4 Hz, 1H), 4.20-3.89(m, 7H), 3.76-3.61 (m, 2H), 2.67-2.51 (m, 1H), 2.39-2.22 (m, 1H), 1.49(d, J = 6.5 Hz, 6H). 323 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J =2.2 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 8.07 (d, J = 5.1Hz, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.29 (p,J = 6.4 Hz, 1H), 4.11 (dd, J = 5.6, 2.2 Hz, 1H), 4.05 (dd, J = 10.7, 5.6Hz, 1H), 3.91 (d, J = 10.2 Hz, 1H), 3.68 (dd, J = 10.6, 2.2 Hz, 1H),3.44 (d, J = 10.2 Hz, 1H), 3.00 (s, 1H), 2.86 (d, J = 0.7 Hz, 1H), 2.70(s, 1H), 1.98 (s, 3H), 1.47 (d, J = 6.4 Hz, 6H), 1.00-0.93 (m, 1H), 0.89(dd, J = 8.3, 5.0 Hz, 1H). 324 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d,J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 8.07 (d, J =5.1 Hz, 1H), 7.87 (s, 1H), 7.23 (dd, J = 5.1, 1.6 Hz, 1H), 4.29 (p, J =6.3 Hz, 1H), 4.11 (dd, J = 5.6, 2.2 Hz, 1H), 4.05 (dd, J = 10.6, 5.6 Hz,1H), 3.91 (d, J = 10.2 Hz, 1H), 3.68 (dd, J = 10.7, 2.3 Hz, 1H), 3.44(d, J = 10.2 Hz, 1H), 1.98 (s, 3H), 1.47 (d, J = 6.4 Hz, 6H), 1.00-0.84(m, 2H). 325 1H NMR (400 MHz, Acetonitrile-d3) δ 9.87 (s, 1H), 8.66 (d,J = 2.1 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H),8.51 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.53(s, 1H), 7.20 (d, J = 5.1 Hz, 1H), 6.68 (dd, J = 2.8, 1.7 Hz, 1H), 4.29(dq, J = 12.9, 6.4 Hz, 1H), 1.45 (d, J = 6.4 Hz, 6H). 326 1H NMR (400MHz, Acetonitrile-d3) δ 9.56 (s, 1H), 9.17 (d, J = 1.7 Hz, 1H), 9.14 (s,2H), 8.66 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.10-8.04 (m, 1H), 7.78 (s,0H), 7.78 (s, 1H), 7.77 (t, J = 1.2 Hz, 1H), 7.55 (s, 1H), 7.25-7.19 (m,1H), 5.35 (t, J = 4.8 Hz, 2H), 2.25 (t, J = 7.6 Hz, 4H), 1.44 (d, J =6.4 Hz, 6H). 327 1H NMR (400 MHz, Acetonitrile-d3) δ 9.94 (d, J = 7.7Hz, 1H), 8.62-8.54 (m, 2H), 8.36 (s, 1H), 8.01 (d, J = 5.1 Hz, 1H), 7.56(s, 1H), 7.16 (d, J = 5.0 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 5.03 (dt, J= 14.5, 8.4 Hz, 2H), 4.20 (dq, J = 13.1, 6.5 Hz, 1H), 3.57-3.49 (m, 1H),1.98 (s, 3H), 1.42 (d, J = 6.4 Hz, 6H). 328 1H NMR (400 MHz,Acetonitrile-d3) δ 9.86 (d, J = 7.8 Hz, 1H), 8.62-8.55 (m, 2H), 8.24 (s,1H), 7.99 (d, J = 5.1 Hz, 1H), 7.43 (s, 1H), 7.17 (d, J = 5.1 Hz, 1H),4.59-4.48 (m, 2H), 4.46-4.36 (m, 3H), 4.21 (dq, J = 7.8, 6.3 Hz, 1H),3.85 (t, J = 11.7 Hz, 2H), 3.67 (t, J = 7.6 Hz, 2H), 2.66 (tt, J = 14.2,7.6 Hz, 2H), 1.38 (d, J = 6.4 Hz, 6H). 329 1H NMR (400 MHz,Acetonitrile-d3) δ 10.08 (d, J = 7.6 Hz, 1H), 8.66- 8.60 (m, 2H), 8.37(s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.59 (s, 1H), 7.20 (dd, J = 5.1, 1.8Hz, 1H), 4.24 (dq, J = 13.2, 6.6 Hz, 2H), 4.05 (d, J = 6.7 Hz, 2H),3.81-3.75 (m, 1H), 3.73-3.67 (m, 2H), 3.58-3.49 (m, 2H), 1.80 (p, J =2.5 Hz, 1H), 1.45 (d, J = 6.4 Hz, 6H). 330 1H NMR (400 MHz,Acetonitrile-d3) δ 10.09 (d, J = 7.7 Hz, 1H), 8.67- 8.61 (m, 2H), 8.30(s, 1H), 8.02 (d, J = 5.1 Hz, 1H), 7.52 (s, 1H), 7.20 (d, J = 5.1 Hz,1H), 6.99 (d, J = 6.9 Hz, 1H), 4.54 (q, J = 5.5 Hz, 1H), 4.32-4.18 (m,1H), 3.83 (dd, J = 10.7, 6.1 Hz, 1H), 3.68 (dtt, J = 13.2, 5.0, 2.8 Hz,2H), 3.46 (dd, J = 10.7, 4.1 Hz, 1H), 1.91 (s, 3H), 1.44 (d, J = 6.4 Hz,6H). 331 1H NMR (400 MHz, Acetonitrile-d3) δ 10.09 (d, J = 7.8 Hz, 1H),8.64 (t, J = 1.6 Hz, 2H), 8.61-8.58 (m, 1H), 8.30 (s, 1H), 8.02 (d, J =5.1 Hz, 1H), 7.52 (s, 1H), 4.54 (dt, J = 11.1, 5.4 Hz, 1H), 4.25 (dq, J= 13.1, 6.4 Hz, 1H), 3.83 (dd, J = 10.7, 6.1 Hz, 1H), 3.72-3.62 (m, 2H),3.46 (dd, J = 10.8, 4.1 Hz, 1H), 1.91 (s, 3H), 1.44 (d, J = 6.4 Hz, 6H),1.36 (d, J = 6.4 Hz, 2H). 332 1H NMR (400 MHz, Acetonitrile-d3) δ 10.42(s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.50 (s,1H), 8.06-8.01 (m, 1H), 7.41 (s, 1H), 7.18 (d, J = 5.1 Hz, 1H),5.16-5.07 (m, 3H), 4.72 (d, J = 2.3 Hz, 2H), 4.63 (dd, J = 8.8, 3.1 Hz,1H), 3.77 (s, 2H), 3.75-3.67 (m, 2H), 3.67-3.55 (m, 2H), 2.55-2.43 (m,1H), 2.23-2.15 (m, 2H), 2.11 (s, 3H). 333 1H NMR (400 MHz,Acetonitrile-d3) δ 9.91 (s, 1H), 8.81 (s, 1H), 8.67- 8.54 (m, 2H), 8.08(d, J = 5.1 Hz, 1H), 8.04-7.84 (m, 1H), 7.18 (d, J = 5.0 Hz, 1H), 4.22(dq, J = 13.1, 6.5 Hz, 1H), 3.36 (tt, J = 10.7, 3.7 Hz, 1H), 3.18-3.07(m, 1H), 2.24 (dd, J = 13.7, 3.9 Hz, 2H), 2.17-2.04 (m, 2H), 1.88 (dt, J= 13.6, 3.9 Hz, 2H), 1.47 (d, J = 6.4 Hz, 6H). 334 1H NMR (400 MHz,Acetonitrile-d3) δ 10.32 (s, 1H), 8.79 (s, 1H), 8.65 (d, J = 2.2 Hz,1H), 8.60 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.62 (s, 1H),7.19 (d, J = 5.0 Hz, 1H), 6.97 (s, 1H), 5.13 (dd, J = 4.0, 2.4 Hz, 3H),4.75 (q, J = 3.8 Hz, 2H), 2.51 (s, 2H), 2.23-2.17 (m, 2H), 2.07 (d, J =7.6 Hz, 1H), 2.05 (dd, J = 3.9, 1.8 Hz, 3H), 1.99 (s, 1H), 1.89 (s, 3H).335 1H NMR (400 MHz, Acetonitrile-d3) δ 10.22 (s, 1H), 8.72 (s, 1H),8.62 (dd, J = 21.6, 2.2 Hz, 2H), 8.06 (d, J = 5.0 Hz, 1H), 7.63 (s, 1H),7.49 (s, 1H), 7.18 (d, J = 5.0 Hz, 1H), 5.13 (d, J = 3.4 Hz, 3H),4.77-4.71 (m, 2H), 2.48 (s, 2H), 2.26-2.20 (m, 2H), 2.12 (s, 2H), 1.36(s, 6H). 336 1H NMR (400 MHz, Acetonitrile-d3) δ 9.90 (s, 1H), 8.69 (d,J = 2.1 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.7 Hz, 1H),8.54 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.55(s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.71 (dd, J = 2.8, 1.7 Hz, 1H), 5.48(s, 2H), 5.38 (t, J = 4.9 Hz, 1H), 4.32 (dq, J = 13.1, 6.5 Hz, 1H),2.30-2.25 (m, 1H), 2.23-2.16 (m, 1H), 2.11 (s, 1H), 2.05 (q, J = 6.7 Hz,3H), 1.47 (d, J = 6.4 Hz, 7H). 337 1H NMR (400 MHz, Acetonitrile-d3) δ10.14 (d, J = 7.7 Hz, 1H), 8.69 (s, 1H), 8.65-8.60 (m, 2H), 8.11 (d, J =5.1 Hz, 1H), 7.80 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 6.71 (s, 1H),4.24-4.14 (m, 1H), 4.01 (dt, J = 12.0, 3.8 Hz, 3H), 3.67 (ddd, J = 12.0,10.6, 2.4 Hz, 3H), 2.19 (dd, J = 10.8, 4.4 Hz, 6H), 2.10 (dd, J = 10.6,4.6 Hz, 6H), 1.32 (s, 6H). 338 1H NMR (400 MHz, Acetonitrile-d3) δ 10.22(d, J = 7.8 Hz, 1H), 8.74- 8.61 (m, 2H), 8.60 (s, 1H), 8.11 (d, J = 5.1Hz, 1H), 7.67 (s, 1H), 7.22 (d, J = 5.1 Hz, 1H), 6.88 (s, 1H), 4.01 (dt,J = 11.9, 3.8 Hz, 2H), 3.67 (td, J = 11.9, 11.4, 2.4 Hz, 2H), 3.60 (s,2H), 3.23 (s, 6H), 2.24-2.07 (m, 15H), 1.87- 1.69 (m, 2H). 339 1H NMR(400 MHz, Acetonitrile-d3) δ 9.70 (s, 1H), 8.73 (s, 1H), 8.62- 8.55 (m,3H), 8.05 (d, J = 4.9 Hz, 2H), 7.99 (s, 1H), 7.17 (d, J = 5.1 Hz, 1H),7.12 (d, J = 8.5 Hz, 1H), 4.18 (dt, J = 13.1, 6.5 Hz, 1H), 3.57 (d, J =3.8 Hz, 2H), 3.31-3.20 (m, 1H), 3.05 (s, 8H), 1.80 (p, J = 2.4 Hz, 2H),1.55-1.49 (m, 1H), 1.46 (d, J = 6.4 Hz, 6H). 340 1H NMR (400 MHz,Acetonitrile-d3) δ 9.52 (s, 1H), 8.70 (s, 1H), 8.58- 8.54 (m, 2H),8.04-7.99 (m, 2H), 7.15 (d, J = 5.0 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H),4.16 (q, J = 6.7 Hz, 1H), 3.76 (s, 1H), 3.50 (d, J = 12.3 Hz, 2H), 3.24(dd, J = 14.2, 10.5 Hz, 2H), 2.86 (s, 2H), 2.76 (s, 4H), 2.06 (d, J =9.2 Hz, 1H), 1.80 (p, J = 2.5 Hz, 2H), 1.45 (d, J = 6.4 Hz, 6H). *Somepeaks are obscured by the water peak 341 1H NMR (400 MHz,Acetonitrile-d3) δ 10.01 (d, J = 7.6 Hz, 1H), 8.69 (s, 1H), 8.67-8.57(m, 2H), 8.09 (d, J = 5.1 Hz, 1H), 7.81 (s, 1H), 7.21 (d, J = 5.1 Hz,1H), 6.64 (d, J = 8.1 Hz, 1H), 4.25 (dq, J = 13.3, 6.7 Hz, 1H), 3.84(ddd, J = 11.7, 7.9, 3.8 Hz, 1H), 3.27 (tt, J = 12.0, 3.6 Hz, 1H),2.15-2.12 (m, 1H), 1.86-1.73 (m, 3H), 1.56 (td, J = 12.6, 3.5 Hz, 2H),1.47 (d, J = 6.4 Hz, 6H), 1.44 (s, 6H). 342 1H NMR (400 MHz,Methanol-d4) δ 8.80 (d, J = 2.1 Hz, 1H), 8.78 (s, 1H), 8.73 (d, J = 2.1Hz, 1H), 8.12 (d, J = 5.0 Hz, 1H), 8.01 (s, 1H), 7.26 (d, J = 5.1 Hz,1H), 4.77 (ddt, J = 7.6, 5.3, 2.7 Hz, 1H), 4.16-4.07 (m, 2H), 3.99 (tt,J = 8.6, 4.0 Hz, 2H), 3.77 (tt, J = 11.7, 4.0 Hz, 1H), 2.62 (ddt, J =13.2, 8.6, 7.1 Hz, 1H), 2.33 (d, J = 13.1 Hz, 2H), 2.23-2.07 (m, 4H),1.97 (s, 3H), 1.82 (qd, J = 13.1, 3.4 Hz, 3H), 1.50 (qd, J = 12.9, 3.4Hz, 2H). 343 1H NMR (400 MHz, Acetonitrile-d3) δ 10.85 (d, J = 46.3 Hz,1H), 10.03 (d, J = 7.5 Hz, 1H), 8.76 (s, 1H), 8.65-8.56 (m, 2H), 8.10(dd, J = 5.1, 2.6 Hz, 1H), 7.93 (s, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.26(s, 1H), 4.21-4.10 (m, 1H), 4.01 (dt, J = 12.0, 3.9 Hz, 2H), 3.66 (td, J= 11.9, 11.4, 2.3 Hz, 2H), 3.49 (d, J = 12.4 Hz, 2H), 3.28 (dd, J = 8.8,5.8 Hz, 1H), 2.92 (s, 1H), 2.80 (s, 1H), 2.75 (d, J = 2.6 Hz, 3H),2.20-2.13 (m, 8H), 2.10-2.03 (m, 5H), 1.84-1.71 (m, 3H).

Compounds comprising the following components or combined with othercomponents exemplified herein might be prepared according to theExamples and Procedures described herein using the appropriate startingmaterials and protecting group chemistry as needed.

R¹ and Het pairings to form the below components present in thesecompounds would be generated from intermediates 1-2 and 1-3. These wouldbe paired with a thiadiazole-R² component.

The above components would be combined with intermediates and componentsattached to the below R² groups and/or to exemplified R² groups by themethods described herein.

Also, any of the exemplified compounds may be made, using, ascomponents, the following “Het” groups:

Biological Assays

Biological assays were conducted to measure activity against TNFα andIRAK4. As summarized in Table 2, the test compounds are inhibitors ofIRAK4.

IRAK4 Monocyte TNFα Cell Based Assay Procedure:

Cryopreserved human monocytes (Stem Cell Technologies) were thawed,diluted in RPMI with GlutaMAX™ (Gibco® 200 mM L-alanyl-L-glutamine) (10mM HEPES, 1× Pen-Strep, 55 μM β-mercaptoethanol, 1 mM Sodium pyruvate)media containing 10% FBS to 0.125 X10⁶ cells/ml and recovered at 37° C.for 2 hours. The cell suspension was then plated at a density of 5,000cells/well onto black 384 well Greiner clear bottom plates. Plates werepre-spotted with test compounds and serially diluted in DMSO where 40nL/well were delivered using the Echo 550 acoustic liquid dispenser(Labcyte®) for a final DMSO concentration of 0.1%. Plated cells weretreated with compound for 1 hour at 37° C. Cells were then stimulatedwith 50 pg/ml of LPS (Sigma) excluding outside columns of plate used forunstimulated cell control wells. Cells were incubated for an additional4 hours at 37° C. Cells were then spun out of the media and 5 μl ofsample were taken and analyzed for total TNFα content using the TR-FRETHuman TNFα detection system (CisBio). This system utilizes two labeledantibodies (cryptate and XL665) that bind to two different epitopes ofthe TNFα molecule and produce FRET signal proportional to theconcentration of TNFα in the sample. Detection antibodies are mixed50:50 and 5 μL were dispensed into each well. Plates were covered withclear seals and incubated at room temp overnight. The following morningplates were read using an Envision 2103 Multilabeled reader(PerkinElmer) with excitation/emission/FRET emission at 340 nm/615nm/665 nm, respectively. Fluorescence intensities at 615 nm and 665 nmemission wavelengths were expressed as a ratio (665 nm/615 nm). Percentof control was calculated as follows:

% Control=100×(Ratio_(Sample)-Ratio_(0% Stimulation))/(Ratio_(100% Stimulation)-Ratio_(0% Stimulation))

where unstimulated cells (0% stimulation) were the negative control andstimulated cells (100% stimulation) were used as the positive control.

IRAK4 Biochemical Assay Procedure:

IRAK4 enzyme (Carna Biosciences, Chuo-ku, Kobe, Japan) activity wasmeasured by detecting phosphorylated peptide substrate formation usingan antibody against the phosphorylated peptide substrate. This is atime-resolved fluorescence resonance energy transfer (TR-FRET)immunoassay, based on the STK1 KinEASE Assay (Cisbio, Bedford,Massachusetts). The assay was designed as a simple two-step, endpointassay (a 5 μl enzyme reaction followed by 5 μl stop and detect Solution)performed in ProxiPlate-384 Plus plates (Perkin Elmer, Waltham, Mass.).Staurosporine, a non-selective kinase inhibitor was used as a positivecontrol. Compounds diluted in DMSO were spotted into 384 well platesusing a Labcyte® Echo 550 Liquid Handling System prior to addition ofIRAK4 enzyme and peptide substrate. Reaction solutions were deliveredusing a Multi-Flo (Bio-Tek Instruments). The enzyme and peptide solutionwas incubated with compound for 15 minutes at room temp before thereaction was initiated by the addition of ATP. The standard 5 μlreaction mixture contained 500 μM ATP, 2 μM peptide (STK1 Peptide), 0.75nM of IRAK4 in reaction buffer (50 mM HEPES, pH 7.0, 0.02% NaN₃, 0.01%BSA, 0.1 mM Orthovanadate, 5 mM MgCl₂, 0.025% NP-40, 1 mM DTT). After120 min of incubation at room temperature, 5 μl of Stop and DetectSolution (1:100 Cryptate labeled anti-phosphorylated peptide antibodysolution and 125 nM Tracer in a 50 mM HEPES pH 7.0 detection buffercontaining sufficient EDTA) was added. The plate was then furtherincubated for 60 minutes at room temperature and read on Envision 2103Multilabeled reader (PerkinElmer) with excitation/emission/FRET emissionat 340 nm/615 nm/665 nm, respectively. Fluorescence intensities at 615nm and 665 nm emission wavelengths were expressed as a ratio (665 nm/615nm). Percentage of inhibition was calculated as below:

% Inhibition=100×(Ratio_(Sample)-Ratio_(0% Inhibition)/(Ratio_(100% Inhibition)-Ratio_(0% Inhibition))

The 0% inhibition value comes from control wells lacking inhibitor. The100% inhibition value comes from control wells containing a saturatingamount of known inhibitor staurosporine.

TABLE 2 Compound EC50 TNF(nM) IC50 HTRF (nM) 1 309 1.5 2 8 1 3 15 <1 423 1 5 76 1 6 19 <1 7 >10000 9 8 7544 9 2128 10 157 <1 11 1171 <1 12 9<1 13 23 <1 14 79 <1 15 3388 <1 16 35 <1 17 55 1 18 >10000 1000 19 58731 20 6 <1 21 10 <1 22 25 <1 23 6 <1 24 14 <1 25 1461 <1 26 305 1 27 67 128 6340 1.7 29 4182 1.8 30 78 1 31 5 <1 32 211 <1 Compound IC₅₀IRAK4-HTBS EC₅₀ MONO TNF HTRF 33 0.49 3971.1 34 0.55 4.9 35 0.87 78.2 360.48 5.0 37 1000.00 10000.0 38 0.80 3.5 39 0.89 10.4 40 3.09 87.6 411.38 11.6 42 1.50 35.7 43 0.72 21.9 44 0.53 27.4 45 1.13 11.8 46 0.6716.7 47 1.42 5675.0 48 1.91 37.5 49 1.75 34.3 50 0.92 3.6 51 1.73 4.7 520.82 4.1 53 0.35 0.6 54 0.73 2.4 55 0.54 115.4 56 0.49 8.3 57 1.16 6.858 1.88 9.3 59 1.97 14.7 60 0.97 8.5 61 1.01 5.3 62 0.38 12.5 63 0.2913.8 64 0.28 6.9 65 0.30 10.6 66 0.42 13.6 67 0.59 10.4 68 0.45 37.9 691.16 11.8 70 0.58 8.8 71 0.58 3.2 72 0.54 2.8 73 0.61 64.1 74 0.54 11.075 0.24 3.2 76 0.85 4.4 77 1.06 3.9 78 0.85 8.9 79 0.48 2.6 80 1.16114.4 81 0.66 21.4 82 1.18 23.1 83 1.37 52.5 84 0.47 8.6 85 1.04 3.3 860.65 0.6 87 0.60 2.1 88 0.83 27.1 89 1.01 11.3 90 1.39 3.6 91 0.93 3.992 1.72 5.0 93 1.78 5.9 94 0.90 4.0 95 0.70 4.1 96 0.58 2.3 97 0.82 21.798 1.13 3.2 99 0.63 5.8 100 0.80 2.1 101 0.89 1.2 102 1.22 31.4 103 0.511.4 104 0.99 1.7 105 0.98 4.2 106 1.09 2.6 107 18.4 108 20.6 109 4.1 1101.8 111 8.8 112 13.1 113 47.4 114 24.4 115 3.5 116 4.1 117 11.1 118 29.0119 1.2 120 121 122 123 124 125 0.25 5.4 126 0.89 26.2 127 0.64 9.9 1280.59 18.8 129 0.59 21.7 130 0.64 18.7 131 0.53 14.3 132 132 Isomer 11.29 12.5 132 Isomer 2 1.30 15.2 133 1.47 531.3 134 0.94 6.9 135 0.5210.5 136 136 Isomer 1 0.57 4.2 136 Isomer 2 0.53 4.0 136 Isomer 3 0.6439.0 136 Isomer 4 0.74 30.5 137 0.85 6.5 138 0.61 15.0 139 0.65 5.9 1400.84 6.4 141 0.50 18.6 142 0.38 9.2 143 0.34 3.1 144 0.63 2.3 145 0.335.6 146 0.48 5.2 147 147 Isomer 1 0.63 8.2 147 Isomer 2 0.62 24.2 1480.31 1.4 149 0.31 4.9 150 0.46 5.2 151 1.03 5.0 152 0.58 10.7 153 0.917.2 154 1.57 13.3 155 1.52 7.4 156 1.42 10.9 157 1.03 1.8 158 1.15 19.8159 6.38 25.7 160 0.52 2.8 161 1.48 34.7 162 2.29 26.5 163 0.54 15.0 1640.55 17.5 165 1.15 39.1 166 0.66 2.3 167 1.81 1000.0 168 0.65 8.4 1690.93 219.5 170 0.36 16.0 171 0.46 2.1 172 2.99 34.4 173 1.52 11.6 1740.49 3.5 175 0.57 9.0 176 0.76 23.5 177 0.41 8.3 178 0.45 4.9 179 0.376.4 180 0.40 6.8 181 0.36 18.4 182 0.53 37.8 183 0.50 8.8 184 0.54 2.4185 186 0.95 8.4 187 0.66 10.8 188 1.07 7.6 189 1.02 16.3 190 1.39 11.7191 1.15 22.9 192 1.21 24.6 193 0.68 4.1 194 0.75 64.0 194 Isomer 1 0.6150.8 194 Isomer 2 0.57 40.6 195 1.09 334.2 196 1.62 107.2 197 1.57 32.9198 0.79 27.4 199 0.69 38.3 200 0.63 24.1 201 1.17 34.9 202 1.23 166.1203 0.83 13.7 204 0.35 3.5 205 0.62 20.1 206 0.56 13.9 207 0.69 7.9 2080.67 13.6 209 0.89 9.6 210 0.84 2.8 211 0.98 78.2 212 1.01 305.4 2130.31 1830.0 214 0.46 33.2 215 0.70 3102.5 216 0.78 18.1 217 0.81 11.1218 1.12 858.4 219 0.68 2073.2 220 1.39 131.2 221 0.92 2320.8 222 1.791780.9 223 1.43 1359.2 224 1.12 4767.2 225 226 227 14.4 228 229 0.6416.5 230 0.74 29.9 231 1.17 22.2 232 0.62 7.4 233 0.35 6.4 234 1.28178.3 235 0.48 4.4 236 0.83 25.8 237 0.14 8.4 238 0.46 12.6 239 0.11 4.9240 0.15 8.9 241 1.39 4.8 242 2.76 752.4 243 0.55 6.4 244 0.93 9.1 2450.55 3.2 246 1.37 43.3 247 0.80 25.1 248 0.93 16.3 249 0.91 8.9 250 1.178.3 251 0.48 4.4 252 0.29 7.0 253 254 255 0.63 5.1 256 0.68 4.6 257 0.9510000.0 258 1.26 5.8 259 0.94 2.6 260 2.56 15.8 261 0.73 18.3 262 3.8169.9 263 1.08 5.1 264 0.59 2.7 265 2.43 11.3 266 0.49 3.2 267 0.65 18.9268 0.61 14.1 269 0.80 5.8 270 0.65 10.7 271 3.22 89.0 272 1.10 4.1 2730.68 4.1 274 1.59 41.0 275 0.78 6.4 276 0.89 7.8 277 0.93 11.3 278 0.0710000.0 279 0.40 15.9 280 1.03 7.4 281 0.40 8281.4 282 0.59 22.4 2830.66 19.9 284 0.69 17.6 285 0.78 68.0 286 0.63 21.4 287 0.86 9.8 2880.72 19.8 289 0.24 21.4 290 0.33 16.2 291 1.78 59.3 292 0.20 6.7 2931.52 364.7 294 1000.0 295 57.69 1000.0 296 1.02 1000.0 297 0.67 10.0 2980.61 36.3 299 0.52 41.6 300 0.98 5.3 301 1.04 4.9 302 0.59 5.3 303 0.5112.5 304 0.54 9.8 305 1.02 15.9 306 1.21 18.4 307 0.83 53.7 308 1.8518.4 309 29.40 687.4 310 0.66 25.9 311 0.80 22.6 312 0.91 17.5 313 1.4748.6 314 0.55 10.1 315 0.77 10.9 316 0.59 5.3 317 0.60 4.4 318 0.94101.8 319 1.68 126.1 320 1.18 68.3 321 1.46 53.5 322 0.31 419.1 323 0.623.7 324 0.99 19.1 325 8.07 1000.0 326 6.01 327 0.37 10.2 328 1.02 80.5329 0.84 54.2 330 1.80 47.1 331 1.21 81.4 332 1.61 434.9 333 1.99 1000.0334 2.41 98.9 335 0.64 48.9 336 0.70 11.0 337 3.3 338 2.7 339 9.1 3409.1 341 72.4 342 343

What is claimed is:
 1. A compound of Formula (I):

wherein “Het” is a bicyclic heteroaryl optionally substituted with X; Xis selected from —H, —F, —Cl, —Br, and —CN; R¹ and R² are eachindependently selected from: a) C₁₋₁₀ alkyl optionally substituted withZ¹; b) C₃₋₁₀ cycloalkyl optionally substituted with Z¹; c) 5-10 memberedheteroaryl optionally substituted with Z¹; d) C₆₋₁₀ aryl optionallysubstituted with Z¹; e) 4-12 membered heterocyclyl optionallysubstituted with Z¹; and f) —H, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,—C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)—R¹²,—N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²)—NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,—OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹²,—S(O)₂R¹², —S(O)₂N(R¹²)(R¹²), or sulfoximine; Z¹ is independently oxo,imino, sulfoximino, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹²)(R¹²),—N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹²,—N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹²)(R¹²),—NR¹²S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²(R¹²), —Si(R¹²)₃,—S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹²)(R¹²); whereinany alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl orheterocyclyl is optionally substituted with Z^(1a); each Z^(1a) isindependently oxo, imino, sulfoximino, halo, —NO₂, —CN, —N₃, C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R¹²,—C(O)N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²) —N(R¹²)—C(O)R¹²,—N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²),—N(R¹²)S(O)₂—N(R¹²)(R¹²), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,—OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹²or —S(O)₂N(R¹²)(R¹²); wherein any alkyl, alkenyl, alkynyl, cycloalkyl,haloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith Z^(1b); each R¹² is independently H, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein anyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl isoptionally substituted with Z^(1a); each Z^(1b) is independently oxo,imino, sulfoximino, hydroxy, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,heteroaryl, heterocyclyl, —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆alkynyl), —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl),—O(heteroaryl), —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆alkenyl), —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl),—NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,—N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl),—N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),—C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),—C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl),—C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂,—C(O)NH(C₁₋₉ alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),—C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),—C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂,—C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl),—NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),—NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),—NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl),—NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl),—NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),—NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl),—S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl),—S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl),—S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl), —S(O)(aryl),—S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₂₋₆alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl),—S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉ alkyl)₂; wherein any alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substitutedwith one or more halo, C₁₋₉ alkyl, C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉alkyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),—NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl),S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl),—S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉alkyl), —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl); or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof.
 2. The compound of claim 1or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein “Het” is selectedfrom:


3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R¹ is C₁₋₁₀ alkyl optionally substituted with Z₁.
 4. Thecompound of claim 1 or 2, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R¹ is C₁₋₅ alkyl optionally substituted with —F, —OH, or —CN. 5.The compound of claim 1 or 2, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R¹ is 4-8 membered heterocycle optionally substituted with Z¹.6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R¹ is oxetane, tetrahydrofuran or tetrahydropyran optionallysubstituted with Z¹.
 7. The compound of claim 1 or 2, or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ is C₃₋₁₀cycloalkyl optionally substituted with Z¹.
 8. The compound of claim 1 or2, or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ is C₃₋₁₀cycloalkyl substituted with 5-10 membered heteroaryl wherein said 5-10membered heteroaryl is optionally substituted with Z^(1a).
 9. Thecompound of claim 1 or 2, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R¹ is C₃₋₁₀ cycloalkyl substituted with C₁₋₃ alkyl and said C₁₋₃alkyl is further substituted with Z^(1a).
 10. The compound of claim 1 or2, or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ is 5-10 memberedheteroaryl optionally substituted with Z¹.
 11. The compound of any oneof claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, or deuterated analog thereof, wherein R² isC₁₋₁₀ alkyl optionally substituted with Z¹.
 12. The compound of any oneof claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, or deuterated analog thereof, wherein R² isC₁₋₁₀ alkyl optionally substituted with one or more —F, —OH orcombinations thereof.
 13. The compound of any one of claims 1 to 10, ora pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R² is C₃₋₁₀cycloalkyl optionally substituted with Z¹.
 14. The compound of any oneof claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, or deuterated analog thereof, wherein R² isC₃₋₈ cycloalkyl optionally substituted with —OH, —N(R¹²)C(O)(R¹²),—N(R¹²)C(O)O(R¹²), or —C(O)N(R¹²)(R¹²).
 15. The compound of any one ofclaims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, or deuterated analog thereof, wherein R² is a4-8 membered heterocyclyl optionally substituted with Z¹.
 16. Thecompound of any one of claims 1 to 10, or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers, or deuterated analogthereof, wherein R² is a 4-8 membered heterocyclyl substituted with —OH,—N(R¹²)C(O)(R¹²), —N(R¹²)C(O)O(R¹²), or —C(O)N(R¹²) (R¹²).
 17. Thecompound of any one of claims 1 to 10 or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers, or deuterated analogthereof, wherein R² is —C(O)—N(R¹²)(R¹²).
 18. A compound of Formula(Ia):

wherein R¹ and R² are each independently selected from: a) C₁₋₁₀ alkyloptionally substituted with Z¹; b) C₃₋₁₀ cycloalkyl optionallysubstituted with Z¹; c) 5-10 membered heteroaryl optionally substitutedwith Z¹; d) C₆₋₁₀ aryl optionally substituted with Z¹; e) 4-12 memberedheterocyclyl optionally substituted with Z¹; and f) —H, —O—R¹²,—C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺,—N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹²)(R¹²),—N(R¹²)S(O)₂(R¹²) —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R¹²), —OC(O)R¹²,—OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,—S(O)(NH)R¹², —S(O)₂R¹², —S(O)₂N(R¹²)(R¹²), or sulfoximino; and whereinZ¹ is independently oxo, imino, sulfoximino, halo, —NO₂, —N₃, —CN, C₁₋₉alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,aryl, heteroaryl, heterocyclyl, —C(O)—R¹², —C(O)O—R¹²,—C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)—R¹²,—N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²),—NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,—OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹²or —S(O)₂N(R¹²)(R¹²); wherein any alkyl, alkenyl, alkynyl, cycloalkyl,haloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith Z^(1a); each Z^(1a) is independently oxo, imino, sulfoximino, halo,—NO₂, —CN, —N₃, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹²,—C(O)R¹², —C(O)O—R¹², —C(O)N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺,—N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹²)(R¹²),—N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹²)(R¹²), —N(R¹²)S(O)₂O(R¹²),—OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,—S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹²)(R¹²); wherein any alkyl,alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl orheterocyclyl is optionally substituted with Z^(1b); each R¹² isindependently H, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein any alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl isoptionally substituted with Z^(1a); each Z^(1b) is independently oxo,imino, sulfoximino, hydroxy, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,heteroaryl, heterocyclyl, —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆alkynyl), —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl),—O(heteroaryl), —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆alkenyl), —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl),—NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,—N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl),—N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅cycloalkyl), —(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),—C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),—C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl),—C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂,—C(O)NH(C₁₋₉ alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),—C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),—C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂,—C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl),—NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),—NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),—NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl),—NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl),—NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),—NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl),—S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl),—S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl),—S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl), —S(O)(aryl),—S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₂₋₆alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl),—S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉ alkyl)₂; wherein any alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substitutedwith one or more halo, C₁₋₉ alkyl, C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉alkyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),—NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl),S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl),—S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉alkyl), —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl); or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof.
 19. The compound of claim18, or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ is C₁₋₁₀ alkyloptionally substituted with Z₁.
 20. The compound of claim 18, or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ is C₁₋₅ alkyloptionally substituted with —F, —OH, or —CN.
 21. The compound of claim18, or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ is 4-8 memberedheterocycle optionally substituted with Z¹.
 22. The compound of claim18, or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ is oxetane,tetrahydrofuran or tetrahydropyran optionally substituted with Z¹. 23.The compound of claim 18, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R¹ is C₃₋₁₀ cycloalkyl optionally substituted with Z¹.
 24. Thecompound of claim 18, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R¹ is C₃₋₁₀ cycloalkyl substituted with 5-10 membered heteroarylwherein said 5-10 membered heteroaryl is optionally substituted withZ^(1a).
 25. The compound of claim 18, or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers, or deuterated analogthereof, wherein R¹ is C₃₋₁₀ cycloalkyl substituted with C₁₋₃ alkyl andsaid C₁₋₃ alkyl is further substituted with Z^(1a).
 26. The compound ofclaim 18, or a pharmaceutically acceptable salt, stereoisomer, mixtureof stereoisomers, or deuterated analog thereof, wherein R¹ is 5-10membered heteroaryl optionally substituted with Z¹.
 27. The compound ofany one of claims 18 to 26, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R² is C₁₋₁₀ alkyl optionally substituted with Z¹.
 28. Thecompound of any one of claims 18 to 26, or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers, or deuterated analogthereof, wherein R² is C₁₋₁₀ alkyl optionally substituted with one ormore —F, —OH or combinations thereof.
 29. The compound of any one ofclaims 18 to 26, or a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, or deuterated analog thereof, wherein R² isC₃₋₁₀ cycloalkyl optionally substituted with Z¹.
 30. The compound of anyone of claims 18 to 26, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or deuterated analog thereof,wherein R² is C₃₋₈ cycloalkyl optionally substituted with —OH,—N(R¹²)C(O)(R¹²), —N(R¹²)C(O)O(R¹²), or —C(O)N(R¹²) (R¹²).
 31. Thecompound of any one of claims 18 to 26, or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers, or deuterated analogthereof, wherein R² is a 4-8 membered heterocyclyl optionallysubstituted with Z¹.
 32. The compound of any one of claims 18 to 26, ora pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R² is—C(O)—N(R¹²)(R¹²).
 33. A pharmaceutical composition comprising acompound of any one of claims 1 to 32 or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers or deuterated analogthereof, together with a pharmaceutically acceptable carrier.
 34. Amethod of treating an inflammatory condition in a patient in needthereof, comprising administering to said patient a compound of any oneof claims 1 to 33 or the composition of claim
 33. 35. The method ofclaim 34, wherein the inflammatory condition is selected from IBD, SLE,Psoriasis and Rheumatoid Arthritis.